Genetic Variant SH3KBP1:p.Asp657Asn (chrX-19536446-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031892.3(SH3KBP1):c.1969G>A(p.Asp657Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000618 in 1,132,450 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000049 ( 0 hom. 0 hem. )

Consequence

SH3KBP1
NM_031892.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.59

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25520295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3KBP1	NM_031892.3 link	c.1969G>A	p.Asp657Asn	missense_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.1969G>A	p.Asp657Asn	missense_variant	Exon 18 of 18	1	NM_031892.3	ENSP00000380921.3		Q96B97-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111943

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34155

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000490

AC:

AN:

1020507

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

304671

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000640

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111943

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34155

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1969G>A (p.D657N) alteration is located in exon 18 (coding exon 18) of the SH3KBP1 gene. This alteration results from a G to A substitution at nucleotide position 1969, causing the aspartic acid (D) at amino acid position 657 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.084

T;.;.;T

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.41

N;N;N;N

REVEL

Benign

0.073

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.074

T;T;T;T

Polyphen

0.30

B;.;.;.

Vest4

0.40

MutPred

0.22

Loss of ubiquitination at K659 (P = 0.0362);.;.;.;

MVP

0.82

MPC

1.3

ClinPred

0.92

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.064

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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