These are the changes I usually make when DM'ing. Other than the racial restrictions these are not setting specific.

Class Changes

UA and homebrew are available on a case-by-case basis except where noted.

Barbarian (Path of the Berserker)

You may use frenzy up to once per short rest without incurring exhaustion--all subsequent uses cause exhaustion penalties as noted.

Races

All PHB races except Drow and Gnomes are available. From Volo's Guide only Aasimar, Hobgoblins, and Yuan-ti Purebloods, are available. Variant Humans and other racial variants are allowed.

Dragonborn can use their breath weapon a number of times equal to their constitution modifier plus one-third of their level (minimum 1) per long rest. They also get darkvision (60 ft).

At your option, you can use the Player Option--Variant Races and Player Option--Regional Backgrounds. This is not required, but you can only use the Regional Backgrounds if you use the Variant Race that matches (for those with variant races).

Downtime

Xanthar's downtime rules are in play. For crafting, see Items and Crafting.

Other

Inspiration

Each player will start with a single Inspiration point. This can be used in one of three ways:

  1. Inspiration can be used to re-roll any dice roll that affects you directly. This could be one of your attack rolls, saving throws, or ability checks or that of another character who is directly affecting you or affected by one of your abilities.
  2. Inspiration can be donated to another player, as long as they do not already have a point of Inspiration.
  3. Inspiration can be used to establish a fact about the situation or setting that must be taken as true. The DM can veto this use--if he does so, the Inspiration is not expended. This new fact cannot contradict anything that has been directly stated at the table already, but can add a wrinkle. For example, you might spend a point to establish that a particular guard is corrupt and can be bribed easily or that a wall is crumbly and can be pulled down to block pursuers.

Inspiration is regained the following ways, but cannot exceed one point at any specific time:

  1. When the group votes that an action was awesome or very in-character (especially if it was non-optimal and caused issues for your character).
  2. When the party takes a long rest in a safe area such as a home base or protected city (no more than once per session).
  3. When the player accepts a complication suggested by another player or the DM based on their character's Bond, Flaw, or Ideal. This should produce a notable worsening of the situation (or at least add a wrinkle that requires some maneuvering around).

The Lucky feat now gives three limited inspiration uses per long rest--these can only be used to re-roll a dice roll. A character with the Lucky feat can store up to 4 points: 1 regular and 3 limited Inspiration.

Variant Rules

Encumbrance is used normally (NO variant encumbrance)
Alignment is not in use.
Combat Maneuvers (Climb onto a bigger creature, Disarm, Overrun, and Shove Aside) are in use.
Feats and Multiclassing are available without restriction.
XP is off--see below for level advancement.
Resting is normal (1 hr short rests/8 hr long rests), although certain occasions may call for modified rest schedules.
Skills may be used with non-traditional abilities.

Advancement

Instead of using XP (in any fashion), you will advance in levels in the following manner.

Each session where the table feels something meaningful happened, each player present will mark one tic under the XP portion of their sheet. When a character has accumulated a number of tics equal to their current level (or 7, whichever is smaller), they will advance in levels.

So, for example, if Bob is level 4, he needs to attend 4 meaningful sessions to reach level 5. A meaningful session may involve combat (or not), exploration, social interaction with other characters, etc.