rs140326137

chr4-2824649-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001122681.2(SH3BP2):c.276C>T(p.Asn92=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,613,440 control chromosomes in the GnomAD database, including 463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., cov: 33)
  • Exomes 𝑓: 0.022 (430 hom.)
• Consequence: SH3BP2 NM_001122681.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.11

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=-0.49).
• BP6: Variant 4-2824649-C-T is Benign according to our data. Variant chr4-2824649-C-T is described in ClinVar as [Benign]. Clinvar id is 348569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-2824649-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0155 (2367/152294) while in subpopulation NFE AF= 0.0247 (1679/68008). AF 95% confidence interval is 0.0237. There are 33 homozygotes in gnomad4. There are 1079 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2367 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.276C>T	p.Asn92=	synonymous_variant	4/13	ENST00000503393.8
SH3BP2	NM_001145856.2	c.447C>T	p.Asn149=	synonymous_variant	4/13
SH3BP2	NM_001145855.2	c.360C>T	p.Asn120=	synonymous_variant	4/13
SH3BP2	NM_003023.4	c.276C>T	p.Asn92=	synonymous_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.276C>T	p.Asn92=	synonymous_variant	4/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2367 AN: 152176 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0143 AC: 3596 AN: 251134 Hom.: 36 AF XY: 0.0142 AC XY: 1934 AN XY: 135790

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.00960

Gnomad ASJ exome AF: 0.00715

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0219 AC: 31938 AN: 1461146 Hom.: 430 Cov.: 31 AF XY: 0.0211 AC XY: 15346 AN XY: 726926

Gnomad4 AFR exome AF: 0.00355

Gnomad4 AMR exome AF: 0.00977

Gnomad4 ASJ exome AF: 0.00700

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.0136

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0155 AC: 2367 AN: 152294 Hom.: 33 Cov.: 33 AF XY: 0.0145 AC XY: 1079 AN XY: 74474

Gnomad4 AFR AF: 0.00602

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.0247

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0188 Hom.: 13

Bravo AF: 0.0151

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0250

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	12
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140326137; hg19: chr4-2826376; COSMIC: COSV62554155; COSMIC: COSV62554155;