rs3213501

Variant names:

• chr4-2824673-T-C
• rs3213501
• NM_001122681.2:c.300T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001122681.2(SH3BP2):​c.300T>C​(p.His100His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 1,613,482 control chromosomes in the GnomAD database, including 442,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49106 hom., cov: 32)
  • Exomes 𝑓: 0.73 (393109 hom.)
• Consequence: SH3BP2 NM_001122681.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 2.40
• Publications: 27 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 4-2824673-T-C is Benign according to our data. Variant chr4-2824673-T-C is described in ClinVar as Benign. ClinVar VariationId is 258894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.300T>C	p.His100His	synonymous_variant	Exon 4 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.471T>C	p.His157His	synonymous_variant	Exon 4 of 13		NP_001139328.1
SH3BP2	NM_001145855.2	c.384T>C	p.His128His	synonymous_variant	Exon 4 of 13		NP_001139327.1
SH3BP2	NM_003023.4	c.300T>C	p.His100His	synonymous_variant	Exon 4 of 13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.300T>C	p.His100His	synonymous_variant	Exon 4 of 13	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.795 AC: 120842 AN: 151986 Hom.: 49039 Cov.: 32

Gnomad AFR AF: 0.951

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.799

Gnomad FIN AF: 0.682

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.725

Gnomad OTH AF: 0.783

GnomAD2 exomes AF: 0.755 AC: 189528 AN: 251054 AF XY: 0.752

Gnomad AFR exome AF: 0.956

Gnomad AMR exome AF: 0.887

Gnomad ASJ exome AF: 0.729

Gnomad EAS exome AF: 0.528

Gnomad FIN exome AF: 0.679

Gnomad NFE exome AF: 0.724

Gnomad OTH exome AF: 0.762

GnomAD4 exome AF: 0.731 AC: 1067538 AN: 1461378 Hom.: 393109 Cov.: 52 AF XY: 0.732 AC XY: 532408 AN XY: 727004

African (AFR) AF: 0.961 AC: 32184 AN: 33478

American (AMR) AF: 0.882 AC: 39424 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 19105 AN: 26136

East Asian (EAS) AF: 0.532 AC: 21105 AN: 39696

South Asian (SAS) AF: 0.811 AC: 69961 AN: 86252

European-Finnish (FIN) AF: 0.683 AC: 36377 AN: 53272

Middle Eastern (MID) AF: 0.854 AC: 4925 AN: 5768

European-Non Finnish (NFE) AF: 0.719 AC: 799512 AN: 1111682

Other (OTH) AF: 0.744 AC: 44945 AN: 60380

GnomAD4 genome AF: 0.795 AC: 120967 AN: 152104 Hom.: 49106 Cov.: 32 AF XY: 0.794 AC XY: 59003 AN XY: 74332

African (AFR) AF: 0.951 AC: 39520 AN: 41544

American (AMR) AF: 0.855 AC: 13079 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2580 AN: 3472

East Asian (EAS) AF: 0.542 AC: 2784 AN: 5134

South Asian (SAS) AF: 0.798 AC: 3853 AN: 4826

European-Finnish (FIN) AF: 0.682 AC: 7210 AN: 10572

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.725 AC: 49283 AN: 67950

Other (OTH) AF: 0.785 AC: 1655 AN: 2108

Alfa AF: 0.759 Hom.: 111873

Bravo AF: 0.813

Asia WGS AF: 0.732 AC: 2546 AN: 3478

EpiCase AF: 0.741

EpiControl AF: 0.739

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 95% of patients studied by a panel of primary immunodeficiencies. Number of patients: 91. Only high quality variants are reported. -

-

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 -

Fibrous dysplasia of jaw Benign:3

Jan 12, 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

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

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. -

Apr 10, 2020

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	-0.65
CADD	Benign	9.7
DANN	Benign	0.63
PhyloP100		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3213501; hg19: chr4-2826400; COSMIC: COSV62554145; COSMIC: COSV62554145;