rs141518457

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001122681.2(SH3BP2):c.937G>A(p.Gly313Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,470 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 5 hom. )

Consequence

SH3BP2
NM_001122681.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06416333).

BP6

Variant 4-2829843-G-A is Benign according to our data. Variant chr4-2829843-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 348582.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=3}. Variant chr4-2829843-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00114 (174/152128) while in subpopulation NFE AF= 0.00207 (141/68014). AF 95% confidence interval is 0.00179. There are 0 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2 link	c.937G>A	p.Gly313Arg	missense_variant	Exon 8 of 13	ENST00000503393.8	NP_001116153.1	P78314-1A0A384N6E5
SH3BP2	NM_001145856.2 link	c.1108G>A	p.Gly370Arg	missense_variant	Exon 8 of 13		NP_001139328.1	P78314-4
SH3BP2	NM_001145855.2 link	c.1021G>A	p.Gly341Arg	missense_variant	Exon 8 of 13		NP_001139327.1	P78314-3
SH3BP2	NM_003023.4 link	c.937G>A	p.Gly313Arg	missense_variant	Exon 8 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.937G>A	p.Gly313Arg	missense_variant	Exon 8 of 13	1	NM_001122681.2	ENSP00000422168.3		P78314-1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000920

AC:

231

AN:

251118

Hom.:

AF XY:

0.000979

AC XY:

133

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00165

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00152

AC:

2223

AN:

1461342

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1097

AN XY:

726994

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.000359

Gnomad4 NFE exome

AF:

0.00186

Gnomad4 OTH exome

AF:

0.00119

GnomAD4 genome

AF:

0.00114

AC:

174

AN:

152128

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.000435

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00207

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.00101

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00107

AC:

130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fibrous dysplasia of jaw

Uncertain:1Benign:2

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SH3BP2 NM_003023.4 exon 8 p.Gly313Arg (c.937G>A): This variant has not been reported in the literature but is present in 0.1% (204/126524) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs141518457). This variant is present in ClinVar (Variation ID:348582) Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:1

Dec 27, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SH3BP2: BS1, BS2 -

Inborn genetic diseases

Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.937G>A (p.G313R) alteration is located in exon 8 (coding exon 7) of the SH3BP2 gene. This alteration results from a G to A substitution at nucleotide position 937, causing the glycine (G) at amino acid position 313 to be replaced by an arginine (R). 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

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;T;T;.;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.82

.;T;.;.;T;T

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.064

T;T;T;T;T;T

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.1

M;.;M;M;.;M

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.2

N;N;N;N;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.016

D;D;D;D;D;D

Sift4G

Benign

0.24

T;T;T;T;T;T

Polyphen

0.99

D;.;D;D;.;D

Vest4

0.55

MutPred

0.45

Loss of helix (P = 0.0076);.;Loss of helix (P = 0.0076);Loss of helix (P = 0.0076);.;Loss of helix (P = 0.0076);

MVP

0.92

MPC

0.73

ClinPred

0.012

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.032

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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