chr4-2830093-T-C

Position:

chr4-2830093-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001122681.2(SH3BP2):c.1187T>C(p.Met396Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,608,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SH3BP2
NM_001122681.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.848

Variant links:

Genes affected

SH3BP2 (HGNC:10825): (SH3 domain binding protein 2) The protein encoded by this gene has an N-terminal pleckstrin homology (PH) domain, an SH3-binding proline-rich region, and a C-terminal SH2 domain. The protein binds to the SH3 domains of several proteins including the ABL1 and SYK protein tyrosine kinases , and functions as a cytoplasmic adaptor protein to positively regulate transcriptional activity in T, natural killer (NK), and basophilic cells. Mutations in this gene result in cherubism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

SH3BP2 links:

SH3BP2 (HGNC:):

SH3BP2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032542467).

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2 linkuse as main transcript	c.1187T>C	p.Met396Thr	missense_variant	8/13	ENST00000503393.8	NP_001116153.1	P78314-1A0A384N6E5
SH3BP2	NM_001145856.2 linkuse as main transcript	c.1358T>C	p.Met453Thr	missense_variant	8/13		NP_001139328.1	P78314-4
SH3BP2	NM_001145855.2 linkuse as main transcript	c.1271T>C	p.Met424Thr	missense_variant	8/13		NP_001139327.1	P78314-3
SH3BP2	NM_003023.4 linkuse as main transcript	c.1187T>C	p.Met396Thr	missense_variant	8/13		NP_003014.3	P78314-1A0A384N6E5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8 linkuse as main transcript	c.1187T>C	p.Met396Thr	missense_variant	8/13	1	NM_001122681.2	ENSP00000422168.3		P78314-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152252

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000334

AC:

AN:

239636

Hom.:

AF XY:

0.0000228

AC XY:

AN XY:

131392

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:

0.0000990

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000462

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1455870

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

724298

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:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74386

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000334

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Fibrous dysplasia of jaw

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2023

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 SH3BP2 protein function. ClinVar contains an entry for this variant (Variation ID: 454490). This variant has not been reported in the literature in individuals affected with SH3BP2-related conditions. This variant is present in population databases (rs749171361, gnomAD 0.01%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 396 of the SH3BP2 protein (p.Met396Thr). 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

0.043

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.26

CADD

Benign

6.8

DANN

Benign

0.15

DEOGEN2

Benign

0.084

T;.;T;T;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00071

LIST_S2

Benign

0.067

.;T;.;.;T;T

M_CAP

Benign

0.060

MetaRNN

Benign

0.033

T;T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

-1.4

N;.;N;N;.;N

PrimateAI

Benign

0.37

PROVEAN

Benign

0.69

N;N;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.83

T;T;T;T;T;T

Sift4G

Benign

0.79

T;T;T;T;T;T

Polyphen

0.0

B;.;B;B;.;B

Vest4

0.019

MutPred

0.31

Gain of glycosylation at M396 (P = 0.003);.;Gain of glycosylation at M396 (P = 0.003);Gain of glycosylation at M396 (P = 0.003);.;Gain of glycosylation at M396 (P = 0.003);

MVP

0.55

MPC

0.19

ClinPred

0.024

GERP RS

3.0

Varity_R

0.039

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

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