rs267607046

Positions:

chr5-172422445-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001017995.3(SH3PXD2B):c.127C>T(p.Arg43Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R43Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SH3PXD2B
NM_001017995.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.19

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 5-172422445-G-A is Pathogenic according to our data. Variant chr5-172422445-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SH3PXD2B	NM_001017995.3 linkuse as main transcript	c.127C>T	p.Arg43Trp	missense_variant	2/13	ENST00000311601.6
SH3PXD2B	NM_001308175.2 linkuse as main transcript	c.127C>T	p.Arg43Trp	missense_variant	2/13
SH3PXD2B	XM_017009351.2 linkuse as main transcript	c.127C>T	p.Arg43Trp	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SH3PXD2B	ENST00000311601.6 linkuse as main transcript	c.127C>T	p.Arg43Trp	missense_variant	2/13	1	NM_001017995.3	P1
SH3PXD2B	ENST00000519643.5 linkuse as main transcript	c.127C>T	p.Arg43Trp	missense_variant	2/13	1
SH3PXD2B	ENST00000636523.1 linkuse as main transcript	c.85C>T	p.Arg29Trp	missense_variant	2/14	5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152164

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248004

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134070

show subpopulations

Gnomad AFR exome

AF:

0.0000627

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460120

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000308

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Frank-Ter Haar syndrome

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 12, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Mar 23, 2022	ACMG classification criteria: PS4 supporting, PM2 moderated, PM3 moderated, PP3 supporting, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 27, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

3.8

.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.97

MutPred

0.93

Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.64

MPC

1.9

ClinPred

1.0

GERP RS

3.3

Varity_R

0.94

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over