FRMD4A

protein-coding

FERM domain containing 4A, the group of FERM domain containing

Gene summary

This gene encodes a FERM domain-containing protein that regulates epithelial cell polarity. It connects ADP ribosylation factor 6 (ARF6) with the Par protein complex, which regulates the remodeling of adherens junctions and linear actin cable formation during epithelial cell polarization. Polymorphisms in this gene are associated with Alzheimer's disease, and also with nicotine dependence. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

Previous symbols:

FRMD4

MANE transcript

NM_018027.5

Inheritance

ClinVar variants

P:3U:184B:45

Top phenotype

Corpus callosum, agenesis of, with facial anomalies and cerebellar ataxia (Fine-Flusser syndrome)

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr10:13,643,706-14,462,142

External References & Databases

Ensembl (ENSG00000151474)

Transcript & Mutation Effects

hg38 • Region Span ~818.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014787

Submitter: PanelApp Australia

severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014787

Submitter: Labcorp Genetics (formerly Invitae)

severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014787

Submitter: Orphanet

severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014787

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Corpus callosum, agenesis of, with facial anomalies and cerebellar ataxia (Fine-Flusser syndrome)AR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25388005

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FRMD4A variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 195

not providedTotal: 45

FRMD4A-related disorderTotal: 15

Severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndromeTotal: 9

MicrocephalyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018027.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				36 clinvar	5 clinvar	41
missense		1 clinvar	177 clinvar	2 clinvar	2 clinvar	182
nonsense			1 clinvar			1
start loss						0
frameshift	1 clinvar	1 clinvar	1 clinvar			3
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	1	2	184	38	7	232

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018027.5	RefSeq	NP_060497.3	23	MANE Select
ENST00000357447.7	Ensembl	ENSP00000350032.2	23	MANE Select
NM_001318336.2	RefSeq	NP_001305265.1	23	Standard
NM_001318337.2	RefSeq	NP_001305266.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

establishment of epithelial cell polarity

Molecular Function

protein binding, bridging

Cellular Component

cytoplasm
cytoskeleton
adherens junction
bicellular tight junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357447
Coding exons: 23
Length: 818436
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.46	447	619	0.722	0.0000398	6702
Missense (PolyPhen)		167	257.14	0.64945		2735
Synonymous	-0.847	288	270	1.07	0.0000199	2022
Loss of Function	6.64	3	57.2	0.0524	0.00000299	657

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000019	0.000018	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Scaffolding protein that regulates epithelial cell polarity by connecting ARF6 activation with the PAR3 complex (By similarity). Plays a redundant role with FRMD4B in epithelial polarization (By similarity). May regulate MAPT secretion by activating ARF6-signaling (PubMed:27044754). {ECO:0000250|UniProtKB:Q8BIE6, ECO:0000269|PubMed:27044754}.;
Disease: DISEASE: Agenesis of the corpus callosum, with facial anomalies and cerebellar ataxia (CCAFCA) [MIM:616819]: An autosomal recessive intellectual disability syndrome characterized by congenital microcephaly, low anterior hairline, bitemporal narrowing, low-set protruding ears, strabismus and tented thick eyebrows with sparse hair in their medial segment. {ECO:0000269|PubMed:25388005}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.0714
RVIS EVS: -1.57
RVIS percentile EVS: 3.17

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.836

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium