SETD5

Chr 3AD

SET domain containing 5

Also known as: MRD23, SETD5A

NCBI Gene: 55209 ENSG00000168137 UniProt: Q9C0A6 OMIM: 615743

The protein is predicted to function as a histone methyltransferase based on its SET domain. Mutations cause intellectual developmental disorder, autosomal dominant 23 through a loss-of-function mechanism. The condition follows an autosomal dominant inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This function of this gene has yet to be determined but based on sequence similarity to other SET domain proteins it may function as a histone methyltransferase. Mutations in this gene have been associated with an autosomal dominant form of intellectual disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 23MIM #615761

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · syndromic complex neurodevelopmental disorder · AD · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 1.000

Z-score 6.70

OE 0.13 (0.08–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.13Z-score

OE missense 0.89 (0.83–0.94)

683 obs / 771.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.08–0.23)

0≤0.351.4

Missense OE?0.89 (0.83–0.94)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 9 / 69.1Missense obs/exp: 683 / 771.5Syn Z: -0.68

Background carrier burden — how many people carry a rare variant somewhere in SETD5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 40

1,823 rare PASS variants

Rare truncating (LoF)

1 in 1,900

105 rare PASS variants

Rare synonymous (reference)

1 in 62

790 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SETD5. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 52	1 in 2,100
South Asian	~43k	1 in 34	1 in 1,300
Remaining (unassigned)	~30k	1 in 42	1 in 1,500
European (Finnish)	~27k	1 in 91	1 in 2,900
Admixed American	~22k	1 in 32	1 in 1,900
African / African American	~21k	1 in 35	1 in 490
East Asian	~20k	1 in 35	1 in 1,600
Ashkenazi Jewish	~13k	1 in 120	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 45	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 17 of 21 coding exons well covered in gnomAD exomes; exons 3, 10, 11, 17 marginal. Genomes: all 21.? see exons ↓