SHROOM4

Chr X

shroom family member 4

Also known as: MRXSSDS, SHAP, shrm4

NCBI Gene: 57477 ENSG00000158352 UniProt: Q9ULL8 OMIM: 300579

The protein regulates cytoskeletal architecture by modulating the spatial distribution of myosin II and plays an important role in development. Mutations cause X-linked Stocco dos Santos syndrome, characterized by cognitive disabilities. This gene is highly constrained against loss-of-function variants (pLI = 1.0), indicating that functional copies are essential for normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the APX/Shroom family, which contain an N-terminal PDZ domain and a C-terminal ASD2 motif. The encoded protein may play a role in cytoskeletal architecture. Mutations in this gene have been linked to the X-linked Stocco dos Santos syndrome characterized by cognitive disabilities. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2017]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Disputed · X-linked complex neurodevelopmental disorder · XL · ClinGen 2021

evidence questions this relationship

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.23LOEUF

pLI 1.000

Z-score 5.31

OE 0.10 (0.05–0.23)

Highly constrained

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

Missense Constraint?

0.95Z-score

OE missense 0.89 (0.82–0.95)

502 obs / 565.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.23)

0≤0.351.4

Missense OE?0.89 (0.82–0.95)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 4 / 40.5Missense obs/exp: 502 / 565.7Syn Z: 0.33

Background carrier burden — how many people carry a rare variant somewhere in SHROOM4?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,098 rare PASS variants

Rare truncating (LoF)

1 in 4,100

54 rare PASS variants

Rare synonymous (reference)

1 in 100

446 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SHROOM4. 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)	~561k	1 in 69	1 in 3,700
South Asian	~36k	1 in 40	1 in 4,900
Remaining (unassigned)	~31k	1 in 38	≈ 1 in 7,400
European (Finnish)	~27k	1 in 190	≈ 1 in 13,000
Admixed American	~23k	1 in 51	≈ 1 in 23,000
African / African American	~21k	1 in 36	1 in 380
East Asian	~20k	1 in 51	1 in 3,300
Ashkenazi Jewish	~13k	1 in 310	none seen
Middle Eastern	~2,758	1 in 42	≈ 1 in 1,300

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 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓