rs73317796

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001017995.3(SH3PXD2B):c.2477C>T(p.Pro826Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,614,176 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0099 ( 26 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 30 hom. )

Consequence

SH3PXD2B
NM_001017995.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.21

Publications

2 publications found

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 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

SH3PXD2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027823448).

BP6

Variant 5-172338628-G-A is Benign according to our data. Variant chr5-172338628-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 352801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00986 (1502/152336) while in subpopulation AFR AF = 0.034 (1412/41574). AF 95% confidence interval is 0.0325. There are 26 homozygotes in GnomAd4. There are 696 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3PXD2B	NM_001017995.3 link	c.2477C>T	p.Pro826Leu	missense_variant	Exon 13 of 13	ENST00000311601.6	NP_001017995.1	A1X283
SH3PXD2B	XM_017009351.2 link	c.2561C>T	p.Pro854Leu	missense_variant	Exon 14 of 14		XP_016864840.1
SH3PXD2B	NM_001308175.2 link	c.1188+7508C>T		intron_variant	Intron 12 of 12		NP_001295104.1	G3V144

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SH3PXD2B	ENST00000311601.6 link	c.2477C>T	p.Pro826Leu	missense_variant	Exon 13 of 13	1	NM_001017995.3	ENSP00000309714.5	A1X283
SH3PXD2B	ENST00000519643.5 link	c.1188+7508C>T		intron_variant	Intron 12 of 12	1		ENSP00000430890.1	G3V144
SH3PXD2B	ENST00000636523.1 link	c.1227+7508C>T		intron_variant	Intron 13 of 13	5		ENSP00000490082.1	A0A1B0GUF2
SH3PXD2B	ENST00000518522.5 link	c.199-4859C>T		intron_variant	Intron 3 of 3	5		ENSP00000428076.1	H0YAU1

Frequencies

GnomAD3 genomes

AF:

0.00985

AC:

1500

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0340

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00451

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00248

AC:

621

AN:

250724

AF XY:

0.00174

show subpopulations

Gnomad AFR exome

AF:

0.0340

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000984

AC:

1438

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000854

AC XY:

621

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0352

AC:

1179

AN:

33476

American (AMR)

AF:

0.00195

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111998

Other (OTH)

AF:

0.00204

AC:

123

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

109

217

326

434

543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00986

AC:

1502

AN:

152336

Hom.:

Cov.:

AF XY:

0.00934

AC XY:

696

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0340

AC:

1412

AN:

41574

American (AMR)

AF:

0.00451

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68030

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

142

213

284

355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00513

Hom.:

Bravo

AF:

0.0119

ESP6500AA

AF:

0.0325

AC:

143

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00315

AC:

382

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2023

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Frank-Ter Haar syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

3.2

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.085

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

0.068

Vest4

0.14

MVP

0.34

MPC

0.19

ClinPred

0.050

GERP RS

4.1

Varity_R

0.11

gMVP

0.44

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over