rs143129053

Positions:

chr4-2830057-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001122681.2(SH3BP2):c.1151G>A(p.Arg384Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,611,748 control chromosomes in the GnomAD database, including 1 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R384W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

SH3BP2
NM_001122681.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.488

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.083494455).

BP6

Variant 4-2830057-G-A is Benign according to our data. Variant chr4-2830057-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 348586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000388 (59/152238) while in subpopulation NFE AF= 0.00075 (51/68044). AF 95% confidence interval is 0.000585. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SH3BP2	NM_001122681.2 linkuse as main transcript	c.1151G>A	p.Arg384Gln	missense_variant	8/13	ENST00000503393.8
SH3BP2	NM_001145856.2 linkuse as main transcript	c.1322G>A	p.Arg441Gln	missense_variant	8/13
SH3BP2	NM_001145855.2 linkuse as main transcript	c.1235G>A	p.Arg412Gln	missense_variant	8/13
SH3BP2	NM_003023.4 linkuse as main transcript	c.1151G>A	p.Arg384Gln	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8 linkuse as main transcript	c.1151G>A	p.Arg384Gln	missense_variant	8/13	1	NM_001122681.2	P2	P78314-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000398

AC:

AN:

243904

Hom.:

AF XY:

0.000473

AC XY:

AN XY:

133238

show subpopulations

Gnomad AFR exome

AF:

0.0000669

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000145

Gnomad NFE exome

AF:

0.000803

Gnomad OTH exome

AF:

0.000665

GnomAD4 exome

AF:

0.000306

AC:

446

AN:

1459510

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

234

AN XY:

726070

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000506

Gnomad4 NFE exome

AF:

0.000353

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000388

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000952

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000474

AC:

ExAC

AF:

0.000571

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fibrous dysplasia of jaw

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 05, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

SH3BP2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;T;T;.;T

Eigen

Benign

-0.071

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.95

.;D;.;.;D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.083

T;T;T;T;T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

2.0

M;.;M;M;.;M

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.78

N;N;N;N;N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.022

D;D;D;D;D;D

Sift4G

Benign

0.59

T;T;T;T;T;T

Polyphen

0.91

P;.;P;P;.;P

Vest4

0.21

MVP

0.94

MPC

0.35

ClinPred

0.0091

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.056

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