NM_031892.3:c.1957A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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. 15/23 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M653L) has been classified 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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency 61
Inheritance: XL, Unknown Classification: LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

SH3KBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

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

BS2

High Hemizygotes in GnomAdExome4 at 25 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031892.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3KBP1	NM_031892.3	MANE Select	c.1957A>G	p.Met653Val	missense splice_region	Exon 18 of 18	NP_114098.1	Q5JPT6
SH3KBP1	NM_001410756.1		c.2089A>G	p.Met697Val	missense splice_region	Exon 20 of 20	NP_001397685.1	Q5JPT2
SH3KBP1	NM_001353891.2		c.2032A>G	p.Met678Val	missense splice_region	Exon 19 of 19	NP_001340820.1	A0A8V8TP27

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3KBP1	ENST00000397821.8	TSL:1 MANE Select	c.1957A>G	p.Met653Val	missense splice_region	Exon 18 of 18	ENSP00000380921.3	Q96B97-1
SH3KBP1	ENST00000379698.8	TSL:1	c.1846A>G	p.Met616Val	missense splice_region	Exon 17 of 17	ENSP00000369020.4	Q96B97-2
SH3KBP1	ENST00000379726.8	TSL:5	c.2089A>G	p.Met697Val	missense splice_region	Exon 20 of 20	ENSP00000369049.4	Q5JPT2

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

112114

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000124

AC:

AN:

161294

AF XY:

0.0000197

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 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

African (AFR)

AF:

0.00

AC:

AN:

24414

American (AMR)

AF:

0.00

AC:

AN:

31536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18104

East Asian (EAS)

AF:

0.00

AC:

AN:

28855

South Asian (SAS)

AF:

0.0000212

AC:

AN:

47255

European-Finnish (FIN)

AF:

0.0000500

AC:

AN:

40017

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3852

European-Non Finnish (NFE)

AF:

0.000110

AC:

AN:

773329

Other (OTH)

AF:

0.0000467

AC:

AN:

42872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30849

American (AMR)

AF:

0.00

AC:

AN:

10573

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3609

South Asian (SAS)

AF:

0.00

AC:

AN:

2702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

53265

Other (OTH)

AF:

0.00

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.11

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0095

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

4.1

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.99

REVEL

Benign

0.17

Sift

Benign

0.57

Sift4G

Benign

1.0

Polyphen

0.38

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

Mutation Taster

=45/55

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over