rs121909150

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_001122681.2(SH3BP2):c.1244G>A(p.Arg415Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,427,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SH3BP2
NM_001122681.2 missense, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.78

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

PP5

Variant 4-2831573-G-A is Pathogenic according to our data. Variant chr4-2831573-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2 link	c.1244G>A	p.Arg415Gln	missense_variant, splice_region_variant	Exon 9 of 13	ENST00000503393.8	NP_001116153.1	P78314-1A0A384N6E5
SH3BP2	NM_001145856.2 link	c.1415G>A	p.Arg472Gln	missense_variant, splice_region_variant	Exon 9 of 13		NP_001139328.1	P78314-4
SH3BP2	NM_001145855.2 link	c.1328G>A	p.Arg443Gln	missense_variant, splice_region_variant	Exon 9 of 13		NP_001139327.1	P78314-3
SH3BP2	NM_003023.4 link	c.1244G>A	p.Arg415Gln	missense_variant, splice_region_variant	Exon 9 of 13		NP_003014.3	P78314-1A0A384N6E5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8 link	c.1244G>A	p.Arg415Gln	missense_variant, splice_region_variant	Exon 9 of 13	1	NM_001122681.2	ENSP00000422168.3		P78314-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1427572

Hom.:

Cov.:

AF XY:

0.00000283

AC XY:

AN XY:

707110

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:

0.00000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00152

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fibrous dysplasia of jaw

Pathogenic:3

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 415 of the SH3BP2 protein (p.Arg415Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cherubism (PMID: 11381256, 21045962, 22795151, 24382142, 24608212, 26064398, 28644570, 30236129). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7551). 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 disruptive. Experimental studies have shown that this missense change affects SH3BP2 function (PMID: 16786512, 22153077). For these reasons, this variant has been classified as Pathogenic. -

Jun 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SH3BP2: PM1:Strong, PM2, PM5, PS4:Moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

D;.;D;D;.;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

.;D;.;.;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.9

N;N;N;N;N;N

REVEL

Pathogenic

0.75

Sift

Uncertain

0.013

D;D;D;D;D;D

Sift4G

Benign

0.27

T;T;T;T;T;T

Polyphen

0.99

D;.;D;D;.;D

Vest4

0.59

MVP

0.96

MPC

0.46

ClinPred

0.95

GERP RS

5.7

Varity_R

0.89

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