NM_001017995.3:c.969delG

Variant names:

• chr5-172350405-GC-G
• rs794728006
• NM_001017995.3:c.969delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001017995.3(SH3PXD2B):​c.969delG​(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
• Publications: 5 publications found

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]

SH3PXD2B Gene-Disease associations (from GenCC):

• Frank-Ter Haar syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 189.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3PXD2B	NM_001017995.3	c.969delG	p.Arg324GlyfsTer19	frameshift_variant	Exon 10 of 13	ENST00000311601.6	NP_001017995.1
SH3PXD2B	NM_001308175.2	c.969delG	p.Arg324GlyfsTer19	frameshift_variant	Exon 10 of 13		NP_001295104.1
SH3PXD2B	XM_017009351.2	c.1053delG	p.Arg352GlyfsTer19	frameshift_variant	Exon 11 of 14		XP_016864840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3PXD2B	ENST00000311601.6	c.969delG	p.Arg324GlyfsTer19	frameshift_variant	Exon 10 of 13	1	NM_001017995.3	ENSP00000309714.5
SH3PXD2B	ENST00000519643.5	c.969delG	p.Arg324GlyfsTer19	frameshift_variant	Exon 10 of 13	1		ENSP00000430890.1
SH3PXD2B	ENST00000636523.1	c.1008delG	p.Arg337fs	frameshift_variant	Exon 11 of 14	5		ENSP00000490082.1
SH3PXD2B	ENST00000518522.5	c.-22delG		upstream_gene_variant		5		ENSP00000428076.1

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

-

Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 12, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 01, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 26, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as homozygous. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.44
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794728006; hg19: chr5-171777409;