4-2829656-T-G

Variant names:

• chr4-2829656-T-G
• rs231399
• NM_001122681.2:c.750T>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001122681.2(SH3BP2):​c.750T>G​(p.Ala250Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,611,582 control chromosomes in the GnomAD database, including 200,283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17057 hom., cov: 29)
  • Exomes 𝑓: 0.50 (183226 hom.)
• Consequence: SH3BP2 NM_001122681.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.742

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-2829656-T-G is Benign according to our data. Variant chr4-2829656-T-G is described in ClinVar as [Benign]. Clinvar id is 258898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-2829656-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.742 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.750T>G	p.Ala250Ala	synonymous_variant	Exon 8 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.921T>G	p.Ala307Ala	synonymous_variant	Exon 8 of 13		NP_001139328.1
SH3BP2	NM_001145855.2	c.834T>G	p.Ala278Ala	synonymous_variant	Exon 8 of 13		NP_001139327.1
SH3BP2	NM_003023.4	c.750T>G	p.Ala250Ala	synonymous_variant	Exon 8 of 13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.750T>G	p.Ala250Ala	synonymous_variant	Exon 8 of 13	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.470 AC: 70975 AN: 151152 Hom.: 17042 Cov.: 29

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.491

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.475

GnomAD3 exomes AF: 0.509 AC: 127187 AN: 250048 Hom.: 33145 AF XY: 0.509 AC XY: 69007 AN XY: 135444

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.642

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.447

Gnomad SAS exome AF: 0.564

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.494

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.499 AC: 728086 AN: 1460314 Hom.: 183226 Cov.: 50 AF XY: 0.500 AC XY: 363530 AN XY: 726488

Gnomad4 AFR exome AF: 0.371

Gnomad4 AMR exome AF: 0.635

Gnomad4 ASJ exome AF: 0.487

Gnomad4 EAS exome AF: 0.461

Gnomad4 SAS exome AF: 0.564

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.495

Gnomad4 OTH exome AF: 0.498

GnomAD4 genome AF: 0.470 AC: 71021 AN: 151268 Hom.: 17057 Cov.: 29 AF XY: 0.473 AC XY: 34933 AN XY: 73864

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.577

Gnomad4 ASJ AF: 0.491

Gnomad4 EAS AF: 0.469

Gnomad4 SAS AF: 0.558

Gnomad4 FIN AF: 0.454

Gnomad4 NFE AF: 0.494

Gnomad4 OTH AF: 0.478

Alfa AF: 0.490 Hom.: 30048

Bravo AF: 0.475

Asia WGS AF: 0.528 AC: 1835 AN: 3478

EpiCase AF: 0.496

EpiControl AF: 0.492

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Benign:5

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 82. Only high quality variants are reported. -

not provided Benign:2 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.35

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

Other links and lift over

dbSNP: rs231399; hg19: chr4-2831383; COSMIC: COSV62553745; COSMIC: COSV62553745;