FMN2

protein-coding

formin 2, the group of Formins

Gene summary

This gene is a member of the formin homology protein family. The encoded protein is thought to have essential roles in organization of the actin cytoskeleton and in cell polarity. This protein mediates the formation of an actin mesh that positions the spindle during oogenesis and also regulates the formation of actin filaments in the nucleus. This protein also forms a perinuclear actin/focal-adhesion system that regulates the shape and position of the nucleus during cell migration. Mutations in this gene have been associated with infertility and also with an autosomal recessive form of intellectual disability (MRT47). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jul 2017]

MANE transcript

NM_020066.5

Inheritance

ClinVar variants

P:22U:228B:334

Top phenotype

Intellectual developmental disorder, autosomal recessive, 47

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr1:240,014,348-240,475,187

External References & Databases

Ensembl (ENSG00000155816)

Transcript & Mutation Effects

hg38 • Region Span ~460.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 47STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014524

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 47STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014524

Submitter: PanelApp Australia

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 47STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014524

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 47STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014524

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive, 47AR

Manifestation: 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: 25480035

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FMN2 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 319

Inborn genetic diseasesTotal: 192

FMN2-related disorderTotal: 139

not specifiedTotal: 131

Intellectual disability, autosomal recessive 47Total: 50

Intellectual disabilityTotal: 4

Neurodevelopmental abnormalityTotal: 2

Aganglionic megacolonTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020066.5. 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			2 clinvar	277 clinvar	9 clinvar	288
missense		1 clinvar	226 clinvar	42 clinvar	3 clinvar	272
nonsense	3 clinvar	9 clinvar				12
start loss						0
frameshift	4 clinvar	5 clinvar		3 clinvar		12
splice donor/acceptor (+/-2bp)						0
Total	7	15	228	322	12	584

Highest pathogenic variant AF is 0.00043441256

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020066.5	RefSeq	NP_064450.3	18	MANE Select
ENST00000319653.14	Ensembl	ENSP00000318884.9	18	MANE Select
NM_001305424.2	RefSeq	NP_001292353.1	19	Standard
NM_001348094.2	RefSeq	NP_001335023.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cellular response to DNA damage stimulus
multicellular organism development
protein transport
vesicle-mediated transport
intracellular signal transduction

Molecular Function

molecular_function
actin binding

Cellular Component

nucleus
nucleolus
endoplasmic reticulum membrane
spindle
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000319653
Coding exons: 18
Length: 460842
Individuals with no LoFs: 122940
Homozygous LoFs: 151
Heterozygous LoFs: 2657
Defined: 125748
p: 0.0112

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.318	856	883	0.970	0.0000466	10847
Missense (PolyPhen)		66	104.56	0.63121		1450
Synonymous	-4.80	493	375	1.32	0.0000225	3753
Loss of Function	6.11	10	61.9	0.162	0.00000322	738

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0088	0.0040	notable
Latino/Admixed American	0.014	0.0064	notable
Ashkenazi Jewish	0.015	0.0063	notable
East Asian	0.032	0.014	notable
Finnish	0.055	0.025	notable
European (Non-Finnish)	0.029	0.013	notable
South Asian	0.011	0.0047	notable
Other	0.027	0.011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Actin-binding protein that is involved in actin cytoskeleton assembly and reorganization (PubMed:22330775, PubMed:21730168). Acts as an actin nucleation factor and promotes assembly of actin filaments together with SPIRE1 and SPIRE2 (PubMed:22330775, PubMed:21730168). Involved in intracellular vesicle transport along actin fibers, providing a novel link between actin cytoskeleton dynamics and intracellular transport (By similarity). Required for asymmetric spindle positioning, asymmetric oocyte division and polar body extrusion during female germ cell meiosis (By similarity). Plays a role in responses to DNA damage, cellular stress and hypoxia by protecting CDKN1A against degradation, and thereby plays a role in stress-induced cell cycle arrest (PubMed:23375502). Also acts in the nucleus: together with SPIRE1 and SPIRE2, promotes assembly of nuclear actin filaments in response to DNA damage in order to facilitate movement of chromatin and repair factors after DNA damage (PubMed:26287480). Protects cells against apoptosis by protecting CDKN1A against degradation (PubMed:23375502). {ECO:0000250|UniProtKB:Q9JL04, ECO:0000269|PubMed:21730168, ECO:0000269|PubMed:22330775, ECO:0000269|PubMed:23375502, ECO:0000269|PubMed:26287480}.;
Disease: DISEASE: Mental retardation, autosomal recessive 47 (MRT47) [MIM:616193]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT47 patients show delayed development, with cognition and speech more affected than motor skills. {ECO:0000269|PubMed:25480035}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.659
RVIS EVS: 0.41
RVIS percentile EVS: 76.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.213

Gene Damage Prediction

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