5-172422467-G-A

Position:

• chr5-172422467-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001017995.3(SH3PXD2B):​c.105C>T​(p.Ser35=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,610,500 control chromosomes in the GnomAD database, including 82,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7494 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74940 hom.)
• Consequence: SH3PXD2B NM_001017995.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.18

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-172422467-G-A is Benign according to our data. Variant chr5-172422467-G-A is described in ClinVar as [Benign]. Clinvar id is 257056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-172422467-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3PXD2B	NM_001017995.3	c.105C>T	p.Ser35=	synonymous_variant	2/13	ENST00000311601.6
SH3PXD2B	NM_001308175.2	c.105C>T	p.Ser35=	synonymous_variant	2/13
SH3PXD2B	XM_017009351.2	c.105C>T	p.Ser35=	synonymous_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3PXD2B	ENST00000311601.6	c.105C>T	p.Ser35=	synonymous_variant	2/13	1	NM_001017995.3	P1
SH3PXD2B	ENST00000519643.5	c.105C>T	p.Ser35=	synonymous_variant	2/13	1
SH3PXD2B	ENST00000636523.1	c.63C>T	p.Ser21=	synonymous_variant	2/14	5

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45702 AN: 151786 Hom.: 7481 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.296

GnomAD3 exomes AF: 0.351 AC: 86604 AN: 246870 Hom.: 17100 AF XY: 0.345 AC XY: 46107 AN XY: 133482

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.670

Gnomad SAS exome AF: 0.384

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.285

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.312 AC: 454464 AN: 1458596 Hom.: 74940 Cov.: 40 AF XY: 0.313 AC XY: 226690 AN XY: 725382

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.483

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.629

Gnomad4 SAS exome AF: 0.382

Gnomad4 FIN exome AF: 0.282

Gnomad4 NFE exome AF: 0.292

Gnomad4 OTH exome AF: 0.324

GnomAD4 genome AF: 0.301 AC: 45745 AN: 151904 Hom.: 7494 Cov.: 32 AF XY: 0.307 AC XY: 22757 AN XY: 74230

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.282

Gnomad4 EAS AF: 0.669

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.269

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.296

Alfa AF: 0.293 Hom.: 12289

Bravo AF: 0.307

Asia WGS AF: 0.468 AC: 1627 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Frank-Ter Haar syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.3
DANN	Benign	0.92

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

Other links and lift over

dbSNP: rs17074773; hg19: chr5-171849471; COSMIC: COSV61128225;