rs749171361

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 17/21 in silico tools predict a benign outcome for this variant. 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. M396V) has been classified 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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

cherubism
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

SH3BP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein
SH3BP2	NM_001122681.2 link	c.1187T>C	p.Met396Thr	missense_variant	Exon 8 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2 link	c.1358T>C	p.Met453Thr	missense_variant	Exon 8 of 13		NP_001139328.1
SH3BP2	NM_001145855.2 link	c.1271T>C	p.Met424Thr	missense_variant	Exon 8 of 13		NP_001139327.1
SH3BP2	NM_003023.4 link	c.1187T>C	p.Met396Thr	missense_variant	Exon 8 of 13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8 link	c.1187T>C	p.Met396Thr	missense_variant	Exon 8 of 13	1	NM_001122681.2	ENSP00000422168.3

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

GnomAD2 exomes

AF:

0.0000334

AC:

AN:

239636

AF XY:

0.0000228

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:

0.0000462

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

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111206

Other (OTH)

AF:

0.00

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000142

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

Oct 22, 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 threonine, which is neutral and polar, at codon 396 of the SH3BP2 protein (p.Met396Thr). This variant is present in population databases (rs749171361, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SH3BP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 454490). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SH3BP2 protein function with a negative predictive value of 80%. 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

(source)

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

0.0

.;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

PhyloP100

0.85

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

Vest4

0.019

ClinPred

0.024

GERP RS

3.0

PromoterAI

-0.048

Neutral

(source)

Varity_R

0.039

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over