X-19536458-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_031892.3(SH3KBP1):c.1957A>G(p.Met653Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000838 in 1,122,348 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000089 ( 0 hom. 25 hem. )

Consequence

SH3KBP1
NM_031892.3 missense, splice_region

Scores

Splicing: ADA: 0.001365

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.13

Variant links:

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]

SH3KBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12324509).

BS2

High Hemizygotes in GnomAdExome4 at 25 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3KBP1	NM_031892.3 link	c.1957A>G	p.Met653Val	missense_variant, splice_region_variant	Exon 18 of 18	ENST00000397821.8	NP_114098.1	Q96B97-1Q5JPT6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3KBP1	ENST00000397821.8 link	c.1957A>G	p.Met653Val	missense_variant, splice_region_variant	Exon 18 of 18	1	NM_031892.3	ENSP00000380921.3		Q96B97-1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

112114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34274

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

161294

Hom.:

AF XY:

0.0000197

AC XY:

AN XY:

50808

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000891

AC:

AN:

1010234

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

297910

show subpopulations

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:

0.0000212

Gnomad4 FIN exome

AF:

0.0000500

Gnomad4 NFE exome

AF:

0.000110

Gnomad4 OTH exome

AF:

0.0000467

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000751

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 653 of the SH3KBP1 protein (p.Met653Val). This variant is present in population databases (rs11248, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SH3KBP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1434001). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.11

T;.;.;T

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Benign

0.0095

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.99

N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.57

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.38

B;.;.;.

Vest4

0.54

MutPred

0.28

Gain of relative solvent accessibility (P = 0.09);.;.;.;

MVP

0.79

MPC

0.56

ClinPred

0.094

GERP RS

4.9

Varity_R

0.27

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0014

dbscSNV1_RF

Benign

0.024

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over