rs3213501

Positions:

• chr4-2824673-T-C

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.300T>C​(p.His100=) 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

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=-0.65).
• BP6: Variant 4-2824673-T-C is Benign according to our data. Variant chr4-2824673-T-C is described in ClinVar as [Benign]. Clinvar id is 258894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-2824673-T-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.300T>C	p.His100=	synonymous_variant	4/13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.471T>C	p.His157=	synonymous_variant	4/13		NP_001139328.1
SH3BP2	NM_001145855.2	c.384T>C	p.His128=	synonymous_variant	4/13		NP_001139327.1
SH3BP2	NM_003023.4	c.300T>C	p.His100=	synonymous_variant	4/13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.300T>C	p.His100=	synonymous_variant	4/13	1	NM_001122681.2	ENSP00000422168	P2

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

GnomAD3 exomes AF: 0.755 AC: 189528 AN: 251054 Hom.: 72925 AF XY: 0.752 AC XY: 102041 AN XY: 135738

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 SAS exome AF: 0.811

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

Gnomad4 AFR exome AF: 0.961

Gnomad4 AMR exome AF: 0.882

Gnomad4 ASJ exome AF: 0.731

Gnomad4 EAS exome AF: 0.532

Gnomad4 SAS exome AF: 0.811

Gnomad4 FIN exome AF: 0.683

Gnomad4 NFE exome AF: 0.719

Gnomad4 OTH exome AF: 0.744

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

Gnomad4 AFR AF: 0.951

Gnomad4 AMR AF: 0.855

Gnomad4 ASJ AF: 0.743

Gnomad4 EAS AF: 0.542

Gnomad4 SAS AF: 0.798

Gnomad4 FIN AF: 0.682

Gnomad4 NFE AF: 0.725

Gnomad4 OTH AF: 0.785

Alfa AF: 0.745 Hom.: 71140

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fibrous dysplasia of jaw Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

not provided Benign:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.7
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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