FRMPD4

protein-coding

FERM and PDZ domain containing 4, the group of PDZ domain containing|FERM domain containing

Gene summary

This gene encodes a multi-domain (WW, PDZ, FERM) containing protein. Through its interaction with other proteins (such as PSD-95), it functions as a positive regulator of dendritic spine morphogenesis and density, and is required for the maintenance of excitatory synaptic transmission. [provided by RefSeq, Jan 2010]

Previous symbols:

PDZK10
PDZD10

MANE transcript

NM_001368397.1

Inheritance

ClinVar variants

P:22U:420B:156

Top phenotype

Intellectual developmental disorder, X-linked 104

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:11,822,423-12,724,523

External References & Databases

Ensembl (ENSG00000169933)

Transcript & Mutation Effects

hg38 • Region Span ~902.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked 104STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010509

Submitter: PanelApp Australia

intellectual developmental disorder, X-linked 104STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010509

Submitter: G2P

intellectual developmental disorder, X-linked 104STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010509

Submitter: Ambry Genetics

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

The *FRMPD4* gene encodes a neural scaffolding protein implicated in the regulation of dendritic spine density and excitatory neurotransmission. *FRMPD4* was first reported in relation to X-linked complex neurodevelopmental disorder in 2016, when a frameshift variant was reported in a multigenerational pedigree with five affected males (Hu et al., PMID: 25644381). Affected males exhibited intellectual disability, delayed or absent speech, variable epilepsy and behavioral abnormalities, while carrier females were unaffected. Two additional families were reported in 2018: two affected brothers with a deletion of exon 2 predicted to result in an in-frame 40 amino-acid deletion, and two affected half-brothers with a nonsense variant (Piard et al., PMID: 29267967). Furthermore, five truncating variants are present in DECIPHER and ClinVar in males with neurodevelopmental disorders. Note that due to technical limitations within the Gene Curation Interface, we are unable to enter and score the in-frame deletion (which is worth 1 point). While *FRMPD4* is intolerant to truncating variants (pLI 1, gnomAD v2.1.1), it is not significantly constrained for missense variants (Z = 1.95). At least 5 rare missense variants have been reported in unrelated males with intellectual disability or autism spectrum disorder (PMIDs: 23020937, 25644381, 25961944, 28263302, 29267967, DECIPHER), but in the absence of functional evidence of pathogenicity, they were not scored. This gene-disease association is also supported by protein interaction, functional alterations in non-patient cells and a mouse model (PMIDs: 19118189, 29267967). In summary, there is definitive evidence supporting the relationship between *FRMPD4* and X-linked complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 2, 2022 (SOP Version 9).

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

intellectual developmental disorder, X-linked 104MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010509

Submitter: Illumina

intellectual developmental disorder, X-linked 104STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010509

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 104XL

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: 25644381

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FRMPD4 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 319

Inborn genetic diseasesTotal: 146

not specifiedTotal: 90

Intellectual disability, X-linked 104Total: 80

FRMPD4-related disorderTotal: 38

Autism, susceptibility to, X-linked 4Total: 2

X-linked complex neurodevelopmental disorderTotal: 2

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001368397.1. 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			28 clinvar	76 clinvar	11 clinvar	115
missense		1 clinvar	373 clinvar	68 clinvar		442
nonsense	3 clinvar	3 clinvar	6 clinvar	1 clinvar		13
start loss						0
frameshift	3 clinvar	8 clinvar	1 clinvar			12
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	12 clinvar			16
Total	7	15	420	145	11	598

Highest pathogenic variant AF is 9.317207e-7

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_001368397.1	RefSeq	NP_001355326.1	17	MANE Select
ENST00000675598.1	Ensembl	ENSP00000502607.1	17	MANE Select
NM_001368395.3	RefSeq	NP_001355324.1	18	Standard
NM_001368396.3	RefSeq	NP_001355325.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of synapse structural plasticity
postsynaptic actin cytoskeleton organization

Molecular Function

protein binding
phosphatidylinositol-4,5-bisphosphate binding

Cellular Component

cytoskeleton
postsynaptic density
protein-containing complex
dendritic spine
glutamatergic synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380682
Coding exons: 17
Length: 586058
Individuals with no LoFs: 124979
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 124980
p: 0.00000400

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.95	414	542	0.764	0.0000443	8659
Missense (PolyPhen)		106	213.89	0.49558		3430
Synonymous	-1.61	263	232	1.13	0.0000212	2638
Loss of Function	5.54	0	35.7	0.00	0.00000264	658

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.00021	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Positive regulator of dendritic spine morphogenesis and density. Required for the maintenance of excitatory synaptic transmission. Binds phosphatidylinositol 4,5-bisphosphate. {ECO:0000269|PubMed:19118189}.;
Disease: DISEASE: Mental retardation, X-linked 104 (MRX104) [MIM:300983]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:25644381}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0975

Intolerance Scores

LoFtool: 0.0193
RVIS EVS: -1.84
RVIS percentile EVS: 2.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.267

Gene Damage Prediction

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