X-19537725-G-A

Variant names:

• chrX-19537725-G-A
• rs748353385
• NM_031892.3:c.1948C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_031892.3(SH3KBP1):​c.1948C>T​(p.Arg650Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,097,447 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000015 (0 hom. 8 hem.)
• Consequence: SH3KBP1 NM_031892.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

Genes affected

SH3KBP1 (HGNC:13867): (SH3 domain containing kinase binding protein 1) This gene encodes an adapter protein that contains one or more N-terminal Src homology domains, a proline rich region and a C-terminal coiled-coil domain. The encoded protein facilitates protein-protein interactions and has been implicated in numerous cellular processes including apoptosis, cytoskeletal rearrangement, cell adhesion and in the regulation of clathrin-dependent endocytosis. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3KBP1	NM_031892.3	c.1948C>T	p.Arg650Trp	missense_variant	Exon 17 of 18	ENST00000397821.8	NP_114098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3KBP1	ENST00000397821.8	c.1948C>T	p.Arg650Trp	missense_variant	Exon 17 of 18	1	NM_031892.3	ENSP00000380921.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1097447 Hom.: 0 Cov.: 29 AF XY: 0.0000221 AC XY: 8 AN XY: 362805

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SH3KBP1 protein function. This variant has not been reported in the literature in individuals affected with SH3KBP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 650 of the SH3KBP1 protein (p.Arg650Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;.;.;T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.2	M;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.60
MutPred		0.34		Loss of disorder (P = 0.0778);.;.;.;
MVP		0.86
MPC		1.4
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.61
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs748353385; hg19: chrX-19555843; COSMIC: COSV65646415;