rs17074644

chr5-172334334-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001017995.3(SH3PXD2B):c.*4035G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0957 in 995,992 control chromosomes in the GnomAD database, including 4,650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (864 hom., cov: 32)
  • Exomes 𝑓: 0.094 (3786 hom.)
• Consequence: SH3PXD2B NM_001017995.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.63

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-172334334-C-T is Benign according to our data. Variant chr5-172334334-C-T is described in ClinVar as [Benign]. Clinvar id is 352738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3PXD2B	NM_001017995.3	c.*4035G>A		3_prime_UTR_variant	13/13	ENST00000311601.6
SH3PXD2B	XM_017009351.2	c.*4035G>A		3_prime_UTR_variant	14/14
SH3PXD2B	NM_001308175.2	c.1189-8954G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3PXD2B	ENST00000311601.6	c.*4035G>A		3_prime_UTR_variant	13/13	1	NM_001017995.3	P1
SH3PXD2B	ENST00000519643.5	c.1189-8954G>A		intron_variant		1
SH3PXD2B	ENST00000518522.5	c.201-565G>A		intron_variant		5
SH3PXD2B	ENST00000636523.1	c.1229-8954G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15945 AN: 152134 Hom.: 860 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0757

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0917

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0990

Gnomad OTH AF: 0.0932

GnomAD4 exome AF: 0.0940 AC: 79293 AN: 843740 Hom.: 3786 Cov.: 32 AF XY: 0.0942 AC XY: 36725 AN XY: 389910

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.0605

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.0896

Gnomad4 FIN exome AF: 0.0938

Gnomad4 NFE exome AF: 0.0932

Gnomad4 OTH exome AF: 0.0985

GnomAD4 genome AF: 0.105 AC: 15980 AN: 152252 Hom.: 864 Cov.: 32 AF XY: 0.104 AC XY: 7749 AN XY: 74452

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0755

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.0918

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0990

Gnomad4 OTH AF: 0.0956

Alfa AF: 0.101 Hom.: 177

Bravo AF: 0.102

Asia WGS AF: 0.109 AC: 379 AN: 3478

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.72
Dann	Benign	0.53

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: rs17074644; hg19: chr5-171761338; COSMIC: COSV61125626; COSMIC: COSV61125626;