rs13356223

Variant names:

• chr5-172394667-T-C
• rs13356223
• NM_001017995.3:c.233-28A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001017995.3(SH3PXD2B):​c.233-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,612,208 control chromosomes in the GnomAD database, including 1,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.062 (433 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1222 hom.)
• Consequence: SH3PXD2B NM_001017995.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.439
• Publications: 3 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), Orphanet, G2P, PanelApp Australia, Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-172394667-T-C is Benign according to our data. Variant chr5-172394667-T-C is described in ClinVar as Benign. ClinVar VariationId is 1249452.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3PXD2B	NM_001017995.3	MANE Select	c.233-28A>G		intron	N/A	NP_001017995.1	A1X283
	SH3PXD2B	NM_001308175.2		c.233-28A>G		intron	N/A	NP_001295104.1	G3V144

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3PXD2B	ENST00000311601.6	TSL:1 MANE Select	c.233-28A>G		intron	N/A	ENSP00000309714.5	A1X283
	SH3PXD2B	ENST00000519643.5	TSL:1	c.233-28A>G		intron	N/A	ENSP00000430890.1	G3V144
	SH3PXD2B	ENST00000918640.1		c.233-28A>G		intron	N/A	ENSP00000588699.1

Frequencies

GnomAD3 genomes AF: 0.0615 AC: 9363 AN: 152126 Hom.: 431 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00975

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0597

GnomAD2 exomes AF: 0.0357 AC: 8921 AN: 249958 AF XY: 0.0333

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0280

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0371

GnomAD4 exome AF: 0.0358 AC: 52270 AN: 1459962 Hom.: 1222 Cov.: 30 AF XY: 0.0347 AC XY: 25182 AN XY: 726404

African (AFR) AF: 0.136 AC: 4562 AN: 33426

American (AMR) AF: 0.0243 AC: 1083 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 1686 AN: 26090

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39672

South Asian (SAS) AF: 0.0109 AC: 938 AN: 86056

European-Finnish (FIN) AF: 0.0315 AC: 1672 AN: 53018

Middle Eastern (MID) AF: 0.0299 AC: 172 AN: 5762

European-Non Finnish (NFE) AF: 0.0356 AC: 39559 AN: 1110956

Other (OTH) AF: 0.0430 AC: 2593 AN: 60344

GnomAD4 genome AF: 0.0616 AC: 9379 AN: 152246 Hom.: 433 Cov.: 32 AF XY: 0.0582 AC XY: 4336 AN XY: 74468

African (AFR) AF: 0.135 AC: 5620 AN: 41516

American (AMR) AF: 0.0398 AC: 609 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 233 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00955 AC: 46 AN: 4818

European-Finnish (FIN) AF: 0.0288 AC: 306 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0357 AC: 2429 AN: 68006

Other (OTH) AF: 0.0591 AC: 125 AN: 2116

Alfa AF: 0.0463 Hom.: 316

Bravo AF: 0.0657

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.5
DANN	Benign	0.54
PhyloP100		0.44
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13356223; hg19: chr5-171821671;