SH2D3C

Chr 9

SH2 domain containing 3C

Also known as: CHAT, NSP3, PRO34088, SHEP1

NCBI Gene: 10044 ENSG00000095370 UniProt: Q8N5H7 OMIM: 604722

SH2D3C encodes an adaptor protein that mediates cell signaling pathways controlling cell adhesion, migration, and immune responses, and is required for olfactory sensory neuron migration and innervation of the olfactory bulb during development. Mutations cause autosomal recessive neurodevelopmental disorder with hypotonia, seizures, and respiratory insufficiency, typically presenting in early infancy. The gene shows very low constraint against loss-of-function variants (pLI 0.0004), consistent with the recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes an adaptor protein and member of a cytoplasmic protein family involved in cell migration. The encoded protein contains a putative Src homology 2 (SH2) domain and guanine nucleotide exchange factor-like domain which allows this signaling protein to form a complex with scaffolding protein Crk-associated substrate. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.59

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.000

Z-score 3.41

OE 0.36 (0.23–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.95Z-score

OE missense 0.76 (0.70–0.83)

415 obs / 542.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.23–0.59)

0≤0.351.4

Missense OE?0.76 (0.70–0.83)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 12 / 33.2Missense obs/exp: 415 / 542.6Syn Z: 0.51

Background carrier burden — how many people carry a rare variant somewhere in SH2D3C?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,137 rare PASS variants

Rare truncating (LoF)

1 in 810

131 rare PASS variants

Rare synonymous (reference)

1 in 80

566 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SH2D3C. 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 58	1 in 920
South Asian	~43k	1 in 28	1 in 710
Remaining (unassigned)	~30k	1 in 40	1 in 640
European (Finnish)	~27k	1 in 130	1 in 2,200
Admixed American	~22k	1 in 51	1 in 540
African / African American	~21k	1 in 43	1 in 720
East Asian	~20k	1 in 53	1 in 310
Ashkenazi Jewish	~13k	1 in 170	1 in 2,200
Middle Eastern	~2,884	1 in 49	≈ 1 in 960

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): All 12 coding exons well covered in gnomAD exomes and genomes.? see exons ↓