chr5-172333565-A-G

Position:

• chr5-172333565-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001017995.3(SH3PXD2B):​c.*4804T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,175,490 control chromosomes in the GnomAD database, including 253,568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.65 (32267 hom., cov: 30)
  • Exomes 𝑓: 0.65 (221301 hom.)
• Consequence: SH3PXD2B NM_001017995.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.05

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 5-172333565-A-G is Benign according to our data. Variant chr5-172333565-A-G is described in ClinVar as [Benign]. Clinvar id is 352729.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3PXD2B	NM_001017995.3	c.*4804T>C		3_prime_UTR_variant	13/13	ENST00000311601.6	NP_001017995.1
SH3PXD2B	XM_017009351.2	c.*4804T>C		3_prime_UTR_variant	14/14		XP_016864840.1
SH3PXD2B	NM_001308175.2	c.1189-8185T>C		intron_variant			NP_001295104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3PXD2B	ENST00000311601.6	c.*4804T>C		3_prime_UTR_variant	13/13	1	NM_001017995.3	ENSP00000309714	P1

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98436 AN: 151224 Hom.: 32227 Cov.: 30

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.647

GnomAD4 exome AF: 0.654 AC: 670040 AN: 1024150 Hom.: 221301 Cov.: 27 AF XY: 0.661 AC XY: 326166 AN XY: 493364

Gnomad4 AFR exome AF: 0.636

Gnomad4 AMR exome AF: 0.644

Gnomad4 ASJ exome AF: 0.690

Gnomad4 EAS exome AF: 0.639

Gnomad4 SAS exome AF: 0.861

Gnomad4 FIN exome AF: 0.605

Gnomad4 NFE exome AF: 0.640

Gnomad4 OTH exome AF: 0.672

GnomAD4 genome AF: 0.651 AC: 98531 AN: 151340 Hom.: 32267 Cov.: 30 AF XY: 0.651 AC XY: 48071 AN XY: 73886

Gnomad4 AFR AF: 0.642

Gnomad4 AMR AF: 0.630

Gnomad4 ASJ AF: 0.696

Gnomad4 EAS AF: 0.653

Gnomad4 SAS AF: 0.845

Gnomad4 FIN AF: 0.600

Gnomad4 NFE AF: 0.653

Gnomad4 OTH AF: 0.647

Alfa AF: 0.639 Hom.: 11241

Bravo AF: 0.644

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Frank-Ter Haar syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.5
DANN	Benign	0.90

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: rs12033; hg19: chr5-171760569; COSMIC: COSV61125622;