5-172358888-A-G

Position:

• chr5-172358888-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001017995.3(SH3PXD2B):​c.563-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,611,944 control chromosomes in the GnomAD database, including 399,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41835 hom., cov: 32)
  • Exomes 𝑓: 0.70 (358012 hom.)
• Consequence: SH3PXD2B NM_001017995.3 intron
• Scores: Splicing: ADA: 0.00008617
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.549

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-172358888-A-G is Benign according to our data. Variant chr5-172358888-A-G is described in ClinVar as [Benign]. Clinvar id is 257058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-172358888-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3PXD2B	NM_001017995.3	c.563-11T>C		intron_variant		ENST00000311601.6	NP_001017995.1
SH3PXD2B	NM_001308175.2	c.563-11T>C		intron_variant			NP_001295104.1
SH3PXD2B	XM_017009351.2	c.563-11T>C		intron_variant			XP_016864840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3PXD2B	ENST00000311601.6	c.563-11T>C		intron_variant		1	NM_001017995.3	ENSP00000309714.5
SH3PXD2B	ENST00000519643.5	c.563-11T>C		intron_variant		1		ENSP00000430890.1
SH3PXD2B	ENST00000636523.1	c.518-11T>C		intron_variant		5		ENSP00000490082.1

Frequencies

GnomAD3 genomes AF: 0.738 AC: 112152 AN: 151988 Hom.: 41782 Cov.: 32

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.731

Gnomad ASJ AF: 0.744

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.723

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.715

GnomAD3 exomes AF: 0.732 AC: 181850 AN: 248446 Hom.: 67173 AF XY: 0.733 AC XY: 98454 AN XY: 134314

Gnomad AFR exome AF: 0.842

Gnomad AMR exome AF: 0.773

Gnomad ASJ exome AF: 0.743

Gnomad EAS exome AF: 0.770

Gnomad SAS exome AF: 0.863

Gnomad FIN exome AF: 0.656

Gnomad NFE exome AF: 0.677

Gnomad OTH exome AF: 0.716

GnomAD4 exome AF: 0.698 AC: 1018910 AN: 1459836 Hom.: 358012 Cov.: 37 AF XY: 0.702 AC XY: 509572 AN XY: 726146

Gnomad4 AFR exome AF: 0.843

Gnomad4 AMR exome AF: 0.768

Gnomad4 ASJ exome AF: 0.742

Gnomad4 EAS exome AF: 0.750

Gnomad4 SAS exome AF: 0.859

Gnomad4 FIN exome AF: 0.661

Gnomad4 NFE exome AF: 0.676

Gnomad4 OTH exome AF: 0.722

GnomAD4 genome AF: 0.738 AC: 112263 AN: 152108 Hom.: 41835 Cov.: 32 AF XY: 0.738 AC XY: 54902 AN XY: 74354

Gnomad4 AFR AF: 0.843

Gnomad4 AMR AF: 0.731

Gnomad4 ASJ AF: 0.744

Gnomad4 EAS AF: 0.772

Gnomad4 SAS AF: 0.856

Gnomad4 FIN AF: 0.656

Gnomad4 NFE AF: 0.680

Gnomad4 OTH AF: 0.714

Alfa AF: 0.697 Hom.: 81784

Bravo AF: 0.743

Asia WGS AF: 0.810 AC: 2816 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	Apr 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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 12, 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

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.28
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000086
dbscSNV1_RF	Benign	0.026
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: rs2569232; hg19: chr5-171785892;