rs28516876

Positions:

• chr4-2827682-G-A
• chr4-2827682-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001122681.2(SH3BP2):​c.586+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0812 in 1,569,274 control chromosomes in the GnomAD database, including 7,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1940 hom., cov: 34)
  • Exomes 𝑓: 0.076 (5346 hom.)
• Consequence: SH3BP2 NM_001122681.2 splice_region, intron
• Scores: Splicing: ADA: 0.001347
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.26

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-2827682-G-A is Benign according to our data. Variant chr4-2827682-G-A is described in ClinVar as [Benign]. Clinvar id is 258897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.586+8G>A		splice_region_variant, intron_variant		ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.757+8G>A		splice_region_variant, intron_variant			NP_001139328.1
SH3BP2	NM_001145855.2	c.670+8G>A		splice_region_variant, intron_variant			NP_001139327.1
SH3BP2	NM_003023.4	c.586+8G>A		splice_region_variant, intron_variant			NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.586+8G>A		splice_region_variant, intron_variant		1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19268 AN: 152106 Hom.: 1933 Cov.: 34

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0741

Gnomad EAS AF: 0.0572

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.0964 AC: 17727 AN: 183976 Hom.: 1175 AF XY: 0.0929 AC XY: 9143 AN XY: 98426

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.0645

Gnomad EAS exome AF: 0.0651

Gnomad SAS exome AF: 0.117

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0694

Gnomad OTH exome AF: 0.0924

GnomAD4 exome AF: 0.0763 AC: 108100 AN: 1417050 Hom.: 5346 Cov.: 35 AF XY: 0.0763 AC XY: 53551 AN XY: 701474

Gnomad4 AFR exome AF: 0.287

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.0635

Gnomad4 EAS exome AF: 0.0584

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0198

Gnomad4 NFE exome AF: 0.0677

Gnomad4 OTH exome AF: 0.0862

GnomAD4 genome AF: 0.127 AC: 19303 AN: 152224 Hom.: 1940 Cov.: 34 AF XY: 0.124 AC XY: 9226 AN XY: 74430

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.0741

Gnomad4 EAS AF: 0.0574

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.0651

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0696 Hom.: 317

Bravo AF: 0.141

Asia WGS AF: 0.107 AC: 375 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Benign:2

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.14		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: rs28516876; hg19: chr4-2829409;