rs62621449

Positions:

• chr5-172339562-C-A
• chr5-172339562-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017995.3(SH3PXD2B):​c.1543G>T​(p.Asp515Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D515N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH3PXD2B NM_001017995.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10363302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3PXD2B	NM_001017995.3	c.1543G>T	p.Asp515Tyr	missense_variant	13/13	ENST00000311601.6	NP_001017995.1
SH3PXD2B	XM_017009351.2	c.1627G>T	p.Asp543Tyr	missense_variant	14/14		XP_016864840.1
SH3PXD2B	NM_001308175.2	c.1188+6574G>T		intron_variant			NP_001295104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3PXD2B	ENST00000311601.6	c.1543G>T	p.Asp515Tyr	missense_variant	13/13	1	NM_001017995.3	ENSP00000309714.5
SH3PXD2B	ENST00000519643.5	c.1188+6574G>T		intron_variant		1		ENSP00000430890.1
SH3PXD2B	ENST00000636523.1	c.1227+6574G>T		intron_variant		5		ENSP00000490082.1
SH3PXD2B	ENST00000518522.5	c.199-5793G>T		intron_variant		5		ENSP00000428076.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.095
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.034	D
Polyphen		0.91	P
Vest4		0.34
MutPred		0.24		Gain of phosphorylation at D515 (P = 0.0015);
MVP		0.37
MPC		0.34
ClinPred		0.41	T
GERP RS		1.8
Varity_R		0.13
gMVP		0.35

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: rs62621449; hg19: chr5-171766566;