rs794728006

chr5-172350405-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001017995.3(SH3PXD2B):c.969del(p.Arg324GlyfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH3PXD2B NM_001017995.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 0.442

Genes affected

SH3PXD2B (HGNC:29242): (SH3 and PX domains 2B) 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-172350405-GC-G is Pathogenic according to our data. Variant chr5-172350405-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 189.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3PXD2B	NM_001017995.3	c.969del	p.Arg324GlyfsTer19	frameshift_variant	10/13	ENST00000311601.6
SH3PXD2B	NM_001308175.2	c.969del	p.Arg324GlyfsTer19	frameshift_variant	10/13
SH3PXD2B	XM_017009351.2	c.1053del	p.Arg352GlyfsTer19	frameshift_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3PXD2B	ENST00000311601.6	c.969del	p.Arg324GlyfsTer19	frameshift_variant	10/13	1	NM_001017995.3	P1
SH3PXD2B	ENST00000519643.5	c.969del	p.Arg324GlyfsTer19	frameshift_variant	10/13	1
SH3PXD2B	ENST00000636523.1	c.1009del	p.Arg338GlyfsTer19	frameshift_variant	11/14	5
SH3PXD2B	ENST00000518522.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

Frank-Ter Haar syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 12, 2010	- -
Likely pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jun 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 26, 2021	This variant was identified as homozygous. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794728006; hg19: chr5-171777409;