FRMD4B

Chr 3

FERM domain containing 4B

Also known as: 6030440G05Rik, GRSP1

NCBI Gene: 23150 ENSG00000114541 UniProt: Q9Y2L6

The protein functions as a scaffolding protein in epithelial cell polarity regulation, connecting ARF6 activation with the PAR3 complex and participating in GRP1 signaling complexes recruited to plasma membrane ruffles during insulin receptor signaling. Mutations cause neurodevelopmental disorders with intellectual disability and developmental delay, inherited in an autosomal recessive pattern. The gene shows significant constraint against loss-of-function variants, suggesting intolerance to complete protein loss.

ResearchSummary from RefSeq, UniProt

This gene encodes a GRP1-binding protein which contains a FERM protein interaction domain as well as two coiled coil domains. This protein may play a role as a scaffolding protein. [provided by RefSeq, Mar 2014]

ResearchGenerating clinical summary…

Clinical highlights

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

0.35

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.35LOEUF

pLI 0.454

Z-score 5.71

OE 0.22 (0.15–0.35)

Highly constrained

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

Missense Constraint?

-0.04Z-score

OE missense 1.00 (0.94–1.08)

547 obs / 544.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.22 (0.15–0.35)

0≤0.351.4

Missense OE?1.00 (0.94–1.08)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 14 / 62.8Missense obs/exp: 547 / 544.3Syn Z: -0.40

Background carrier burden — how many people carry a rare variant somewhere in FRMD4B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 28

1,489 rare PASS variants

Rare truncating (LoF)

1 in 1,300

166 rare PASS variants

Rare synonymous (reference)

1 in 92

554 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FRMD4B. 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 38	1 in 1,500
South Asian	~43k	1 in 40	1 in 1,700
Remaining (unassigned)	~30k	1 in 25	1 in 2,500
European (Finnish)	~27k	1 in 160	1 in 2,000
Admixed American	~22k	1 in 30	1 in 1,900
African / African American	~21k	1 in 36	1 in 1,200
East Asian	~20k	1 in 47	1 in 780
Ashkenazi Jewish	~13k	1 in 120	none seen
Middle Eastern	~2,884	1 in 39	≈ 1 in 2,900

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): 8 of 23 coding exons well covered in gnomAD exomes; exon 10 poorly covered; exons 2, 3, 4, 5, 6 and 9 more marginal. Genomes: all 23.? see exons ↓