rs231402

chr4-2820740-G-T

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.123G>T(p.Leu41=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 1,612,980 control chromosomes in the GnomAD database, including 161,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (12158 hom., cov: 34)
  • Exomes 𝑓: 0.45 (149136 hom.)
• Consequence: SH3BP2 NM_001122681.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 2.21

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=-0.55).
• BP6: Variant 4-2820740-G-T is Benign according to our data. Variant chr4-2820740-G-T is described in ClinVar as [Benign]. Clinvar id is 258893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-2820740-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.123G>T	p.Leu41=	synonymous_variant	2/13	ENST00000503393.8
SH3BP2	NM_001145856.2	c.294G>T	p.Leu98=	synonymous_variant	2/13
SH3BP2	NM_001145855.2	c.207G>T	p.Leu69=	synonymous_variant	2/13
SH3BP2	NM_003023.4	c.123G>T	p.Leu41=	synonymous_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.123G>T	p.Leu41=	synonymous_variant	2/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56862 AN: 152064 Hom.: 12148 Cov.: 34

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.615

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.381

GnomAD3 exomes AF: 0.453 AC: 112803 AN: 249080 Hom.: 26909 AF XY: 0.455 AC XY: 61294 AN XY: 134702

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.605

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.447

Gnomad SAS exome AF: 0.491

Gnomad FIN exome AF: 0.439

Gnomad NFE exome AF: 0.448

Gnomad OTH exome AF: 0.455

GnomAD4 exome AF: 0.447 AC: 653342 AN: 1460798 Hom.: 149136 Cov.: 49 AF XY: 0.449 AC XY: 325965 AN XY: 726656

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.597

Gnomad4 ASJ exome AF: 0.408

Gnomad4 EAS exome AF: 0.456

Gnomad4 SAS exome AF: 0.493

Gnomad4 FIN exome AF: 0.441

Gnomad4 NFE exome AF: 0.449

Gnomad4 OTH exome AF: 0.435

GnomAD4 genome AF: 0.374 AC: 56881 AN: 152182 Hom.: 12158 Cov.: 34 AF XY: 0.380 AC XY: 28243 AN XY: 74394

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.517

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.463

Gnomad4 SAS AF: 0.496

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.446

Gnomad4 OTH AF: 0.383

Alfa AF: 0.420 Hom.: 8953

Bravo AF: 0.372

Asia WGS AF: 0.477 AC: 1658 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 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	PreventionGenetics, part of Exact Sciences	-	- -
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 84% of patients studied by a panel of primary immunodeficiencies. Number of patients: 81. Only high quality variants are reported. -

Fibrous dysplasia of jaw Benign:3

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

not provided Benign:1 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	May 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	9.6
Dann	Benign	0.79

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: rs231402; hg19: chr4-2822467; COSMIC: COSV62553730; COSMIC: COSV62553730;