rs17074773

Variant names:

• chr5-172422467-G-A
• rs17074773
• NM_001017995.3:c.105C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001017995.3(SH3PXD2B):​c.105C>T​(p.Ser35Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,610,500 control chromosomes in the GnomAD database, including 82,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7494 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74940 hom.)
• Consequence: SH3PXD2B NM_001017995.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.18
• Publications: 20 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-172422467-G-A is Benign according to our data. Variant chr5-172422467-G-A is described in ClinVar as Benign. ClinVar VariationId is 257056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.65 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.105C>T	p.Ser35Ser	synonymous	Exon 2 of 13	NP_001017995.1	A1X283
	SH3PXD2B	NM_001308175.2		c.105C>T	p.Ser35Ser	synonymous	Exon 2 of 13	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.105C>T	p.Ser35Ser	synonymous	Exon 2 of 13	ENSP00000309714.5	A1X283
	SH3PXD2B	ENST00000519643.5	TSL:1	c.105C>T	p.Ser35Ser	synonymous	Exon 2 of 13	ENSP00000430890.1	G3V144
	SH3PXD2B	ENST00000918640.1		c.105C>T	p.Ser35Ser	synonymous	Exon 2 of 14	ENSP00000588699.1

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45702 AN: 151786 Hom.: 7481 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.296

GnomAD2 exomes AF: 0.351 AC: 86604 AN: 246870 AF XY: 0.345

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.670

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.285

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.312 AC: 454464 AN: 1458596 Hom.: 74940 Cov.: 40 AF XY: 0.313 AC XY: 226690 AN XY: 725382

African (AFR) AF: 0.247 AC: 8247 AN: 33454

American (AMR) AF: 0.483 AC: 21437 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7303 AN: 26088

East Asian (EAS) AF: 0.629 AC: 24935 AN: 39666

South Asian (SAS) AF: 0.382 AC: 32759 AN: 85716

European-Finnish (FIN) AF: 0.282 AC: 14790 AN: 52528

Middle Eastern (MID) AF: 0.273 AC: 1575 AN: 5762

European-Non Finnish (NFE) AF: 0.292 AC: 323873 AN: 1110688

Other (OTH) AF: 0.324 AC: 19545 AN: 60294

GnomAD4 genome AF: 0.301 AC: 45745 AN: 151904 Hom.: 7494 Cov.: 32 AF XY: 0.307 AC XY: 22757 AN XY: 74230

African (AFR) AF: 0.243 AC: 10055 AN: 41434

American (AMR) AF: 0.387 AC: 5897 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 977 AN: 3470

East Asian (EAS) AF: 0.669 AC: 3452 AN: 5160

South Asian (SAS) AF: 0.380 AC: 1817 AN: 4780

European-Finnish (FIN) AF: 0.269 AC: 2839 AN: 10556

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.292 AC: 19815 AN: 67944

Other (OTH) AF: 0.296 AC: 625 AN: 2114

Alfa AF: 0.294 Hom.: 20050

Bravo AF: 0.307

Asia WGS AF: 0.468 AC: 1627 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Frank-Ter Haar syndrome (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.3
DANN	Benign	0.92
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17074773; hg19: chr5-171849471; COSMIC: COSV61128225;