chr5-172358888-A-G

Variant names:

• chr5-172358888-A-G
• rs2569232
• NM_001017995.3:c.563-11T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017995.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3PXD2B	NM_001017995.3	MANE Select	c.563-11T>C		intron	N/A	NP_001017995.1
	SH3PXD2B	NM_001308175.2		c.563-11T>C		intron	N/A	NP_001295104.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3PXD2B	ENST00000311601.6	TSL:1 MANE Select	c.563-11T>C		intron	N/A	ENSP00000309714.5
	SH3PXD2B	ENST00000519643.5	TSL:1	c.563-11T>C		intron	N/A	ENSP00000430890.1
	SH3PXD2B	ENST00000636523.1	TSL:5	c.518-11T>C		intron	N/A	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

GnomAD2 exomes AF: 0.732 AC: 181850 AN: 248446 AF XY: 0.733

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 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

African (AFR) AF: 0.843 AC: 28175 AN: 33430

American (AMR) AF: 0.768 AC: 34206 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 19363 AN: 26084

East Asian (EAS) AF: 0.750 AC: 29709 AN: 39636

South Asian (SAS) AF: 0.859 AC: 73878 AN: 86036

European-Finnish (FIN) AF: 0.661 AC: 35205 AN: 53300

Middle Eastern (MID) AF: 0.739 AC: 4257 AN: 5762

European-Non Finnish (NFE) AF: 0.676 AC: 750594 AN: 1110756

Other (OTH) AF: 0.722 AC: 43523 AN: 60306

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

African (AFR) AF: 0.843 AC: 34989 AN: 41526

American (AMR) AF: 0.731 AC: 11174 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 2582 AN: 3470

East Asian (EAS) AF: 0.772 AC: 3979 AN: 5154

South Asian (SAS) AF: 0.856 AC: 4124 AN: 4820

European-Finnish (FIN) AF: 0.656 AC: 6932 AN: 10566

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.680 AC: 46198 AN: 67976

Other (OTH) AF: 0.714 AC: 1510 AN: 2114

Alfa AF: 0.700 Hom.: 166291

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Frank-Ter Haar syndrome Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.28
DANN	Benign	0.50
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2569232; hg19: chr5-171785892;