SH3PXD2B

protein-coding

SH3 and PX domains 2B

Gene summary

This gene encodes an adapter protein that is characterized by a PX domain and four Src homology 3 domains. The encoded protein is required for podosome formation and is involved in cell adhesion and migration of numerous cell types. Mutations in this gene are the cause of Frank-ter Haar syndrome (FTHS), and also Borrone Dermato-Cardio-Skeletal (BDCS) syndrome. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

Previous symbols:

KIAA1295

MANE transcript

NM_001017995.3

Inheritance

ClinVar variants

P:18U:252B:165

Top phenotype

Frank-ter Haar syndrome

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr5:172,325,000-172,454,525

External References & Databases

Ensembl (ENSG00000174705)

Transcript & Mutation Effects

hg38 • Region Span ~129.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Frank-Ter Haar syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009579

Submitter: PanelApp Australia

Frank-Ter Haar syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009579

Submitter: Orphanet

Frank-Ter Haar syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009579

Submitter: Genomics England PanelApp

Frank-Ter Haar syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009579

Submitter: Labcorp Genetics (formerly Invitae)

Frank-Ter Haar syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009579

Submitter: ClinGen

The SH3PXD2B gene is located on chromosome 5 at 5q35.1 and encodes SH3 and PX domains-containing protein 2B, which is an adapter protein involved in invadopodia and podosome formation and extracellular matrix degradation. SH3PXD2B was first reported in relation to autosomal recessive Frank-ter Haar syndrome (FTHS) in 2010 (Iqbal et al., 2010, PMID: 20137777). FTHS is a syndromic disorder characterized by brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. At least two nonsense, three frameshift, one missense, one exonic deletion, and one splice site variants that have been reported in seven probands in three publications (PMID: 20137777; Wilson et al., 2014, PMID: 24105366, Zrhidri et al., 2017, PMID: 28694206) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence including a mouse model, functional alteration in patient cells, and rescue in cell culture experiments (PMID: 20137777; Buschman et al., 2009, PMID: 19144821). In summary, there is definitive evidence to support the relationship between SH3PXD2B and autosomal recessive Frank-ter Haar syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on 02.01.2023 (SOP Version 9).

Frank-Ter Haar syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009579

Submitter: G2P

Clinical Genomic Database (CGD)

Frank-ter Haar syndromeAR

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Cardiovascular; Ophthalmologic; Pharmacogenomic

Rationale: The condition may be clinically recognizable, but can include macrocornea with or without glaucoma, and surveillance and prompt treatment may be beneficial; Awareness of cardiac anomalies may allow prompt management; Agents that may contribute to glaucoma should be avoided

Refs: 4805907; 7158646; 9375925; 9188664; 15523657; 20137777; 24105366

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SH3PXD2B variants in ClinVar

5 Conditions Cataloged

not providedTotal: 380

Inborn genetic diseasesTotal: 160

Frank-Ter Haar syndromeTotal: 83

not specifiedTotal: 35

SH3PXD2B-related disorderTotal: 34

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001017995.3. 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	126 clinvar	4 clinvar	132
missense		2 clinvar	237 clinvar	28 clinvar	6 clinvar	273
nonsense	1 clinvar	2 clinvar	2 clinvar			5
start loss						0
frameshift	5 clinvar	2 clinvar	8 clinvar	1 clinvar		16
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	3 clinvar			9
Total	8	10	252	155	10	435

Highest pathogenic variant AF is 0.000010544048

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001017995.3	RefSeq	NP_001017995.1	13	MANE Select
ENST00000311601.6	Ensembl	ENSP00000309714.5	13	MANE Select
NM_001308175.2	RefSeq	NP_001295104.1	13	Standard
ENST00000518522.5	Ensembl	ENSP00000428076.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

skeletal system development
eye development
osteoblast fate commitment
superoxide metabolic process
heart development

Molecular Function

protein binding
phosphatidylinositol-5-phosphate binding
superoxide-generating NADPH oxidase activator activity
phosphatidylinositol-3-phosphate binding
phosphatidylinositol binding

Cellular Component

podosome
cytoplasm
cell junction
cell projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000311601
Coding exons: 13
Length: 129343
Individuals with no LoFs: 125568
Homozygous LoFs: 0
Heterozygous LoFs: 180
Defined: 125748
p: 0.000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.526	511	546	0.937	0.0000347	5925
Missense (PolyPhen)		159	204.39	0.77791		2252
Synonymous	0.830	213	229	0.930	0.0000162	1817
Loss of Function	4.08	12	39.8	0.301	0.00000198	465

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000066	0.000062	rare
Latino/Admixed American	0.00064	0.00064	rare
Ashkenazi Jewish	0.0057	0.0057	notable
East Asian	0.00016	0.00016	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00055	0.00055	rare
South Asian	0.00056	0.00056	rare
Other	0.0021	0.0021	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adapter protein involved in invadopodia and podosome formation and extracellular matrix degradation. Binds matrix metalloproteinases (ADAMs), NADPH oxidases (NOXs) and phosphoinositides. Acts as an organizer protein that allows NOX1- or NOX3-dependent reactive oxygen species (ROS) generation and ROS localization. Plays a role in mitotic clonal expansion during the immediate early stage of adipocyte differentiation (By similarity). {ECO:0000250, ECO:0000269|PubMed:12615925, ECO:0000269|PubMed:19755710, ECO:0000269|PubMed:20609497}.;
Disease: DISEASE: Frank-Ter Haar syndrome (FTHS) [MIM:249420]: A syndrome characterized by brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones and flexion deformity of the fingers. {ECO:0000269|PubMed:20137777}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.628
RVIS EVS: -0.28
RVIS percentile EVS: 33.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.128

Gene Damage Prediction

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