5-172338916-G-C

Variant names:

• chr5-172338916-G-C
• rs766153965
• NM_001017995.3:c.2189C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017995.3(SH3PXD2B):​c.2189C>G​(p.Pro730Arg) 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. 15/22 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. P730L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH3PXD2B NM_001017995.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.753
• Publications: 0 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), ClinGen, Genomics England PanelApp, G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10679546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3PXD2B	NM_001017995.3	c.2189C>G	p.Pro730Arg	missense_variant	Exon 13 of 13	ENST00000311601.6	NP_001017995.1
SH3PXD2B	XM_017009351.2	c.2273C>G	p.Pro758Arg	missense_variant	Exon 14 of 14		XP_016864840.1
SH3PXD2B	NM_001308175.2	c.1188+7220C>G		intron_variant	Intron 12 of 12		NP_001295104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3PXD2B	ENST00000311601.6	c.2189C>G	p.Pro730Arg	missense_variant	Exon 13 of 13	1	NM_001017995.3	ENSP00000309714.5
SH3PXD2B	ENST00000519643.5	c.1188+7220C>G		intron_variant	Intron 12 of 12	1		ENSP00000430890.1
SH3PXD2B	ENST00000636523.1	c.1227+7220C>G		intron_variant	Intron 13 of 13	5		ENSP00000490082.1
SH3PXD2B	ENST00000518522.5	c.199-5147C>G		intron_variant	Intron 3 of 3	5		ENSP00000428076.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.75
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.050
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.33	T
Polyphen		0.42	B
Vest4		0.19
MutPred		0.27		Gain of MoRF binding (P = 6e-04);
MVP		0.19
MPC		0.50
ClinPred		0.73	D
GERP RS		2.7
Varity_R		0.15
gMVP		0.28
Mutation Taster		=98/2	polymorphism

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: rs766153965; hg19: chr5-171765920;