5-172382035-C-T

Position:

• chr5-172382035-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001017995.3(SH3PXD2B):​c.401+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH3PXD2B NM_001017995.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.57

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 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-172382035-C-T is Pathogenic according to our data. Variant chr5-172382035-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 55933.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3PXD2B	NM_001017995.3	c.401+1G>A		splice_donor_variant, intron_variant		ENST00000311601.6	NP_001017995.1
SH3PXD2B	NM_001308175.2	c.401+1G>A		splice_donor_variant, intron_variant			NP_001295104.1
SH3PXD2B	XM_017009351.2	c.401+1G>A		splice_donor_variant, intron_variant			XP_016864840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3PXD2B	ENST00000311601.6	c.401+1G>A		splice_donor_variant, intron_variant		1	NM_001017995.3	ENSP00000309714.5
SH3PXD2B	ENST00000519643.5	c.401+1G>A		splice_donor_variant, intron_variant		1		ENSP00000430890.1
SH3PXD2B	ENST00000636523.1	c.356+1G>A		splice_donor_variant, intron_variant		5		ENSP00000490082.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00426 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Frank-Ter Haar syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2014	- -
Pathogenic, no assertion criteria provided	literature only	Neurogenetics Research; Murdoch Childrens Research Institute	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs367543284; hg19: chr5-171809039;