rs794728006

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017995.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3PXD2B	NM_001017995.3	MANE Select	c.969delG	p.Arg324GlyfsTer19	frameshift	Exon 10 of 13	NP_001017995.1
	SH3PXD2B	NM_001308175.2		c.969delG	p.Arg324GlyfsTer19	frameshift	Exon 10 of 13	NP_001295104.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3PXD2B	ENST00000311601.6	TSL:1 MANE Select	c.969delG	p.Arg324GlyfsTer19	frameshift	Exon 10 of 13	ENSP00000309714.5
	SH3PXD2B	ENST00000519643.5	TSL:1	c.969delG	p.Arg324GlyfsTer19	frameshift	Exon 10 of 13	ENSP00000430890.1
	SH3PXD2B	ENST00000918640.1		c.1071delG	p.Arg358GlyfsTer19	frameshift	Exon 11 of 14	ENSP00000588699.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
4	-	-	Frank-Ter Haar syndrome (4)

Computational scores

Source: dbNSFP v4.9

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;