rs28516876

Variant names:

• chr4-2827682-G-A
• rs28516876
• NM_001122681.2:c.586+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-2827682-G-A
• chr4-2827682-G-C
• chr4-2827682-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	NM_001122681.2	MANE Select	c.586+8G>A		splice_region intron	N/A	NP_001116153.1
	SH3BP2	NM_001145856.2		c.757+8G>A		splice_region intron	N/A	NP_001139328.1
	SH3BP2	NM_001145855.2		c.670+8G>A		splice_region intron	N/A	NP_001139327.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.586+8G>A		splice_region intron	N/A	ENSP00000422168.3
	SH3BP2	ENST00000511747.6	TSL:1	c.757+8G>A		splice_region intron	N/A	ENSP00000424846.2
	SH3BP2	ENST00000356331.10	TSL:1	n.847+8G>A		splice_region intron	N/A

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

GnomAD2 exomes AF: 0.0964 AC: 17727 AN: 183976 AF XY: 0.0929

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 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

African (AFR) AF: 0.287 AC: 9385 AN: 32662

American (AMR) AF: 0.140 AC: 5473 AN: 38964

Ashkenazi Jewish (ASJ) AF: 0.0635 AC: 1610 AN: 25354

East Asian (EAS) AF: 0.0584 AC: 2206 AN: 37802

South Asian (SAS) AF: 0.114 AC: 9244 AN: 81062

European-Finnish (FIN) AF: 0.0198 AC: 1002 AN: 50630

Middle Eastern (MID) AF: 0.107 AC: 611 AN: 5706

European-Non Finnish (NFE) AF: 0.0677 AC: 73510 AN: 1086208

Other (OTH) AF: 0.0862 AC: 5059 AN: 58662

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

African (AFR) AF: 0.274 AC: 11390 AN: 41496

American (AMR) AF: 0.124 AC: 1891 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0741 AC: 257 AN: 3468

East Asian (EAS) AF: 0.0574 AC: 297 AN: 5178

South Asian (SAS) AF: 0.113 AC: 544 AN: 4826

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10620

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0651 AC: 4425 AN: 68012

Other (OTH) AF: 0.109 AC: 230 AN: 2116

Alfa AF: 0.0696 Hom.: 317

Bravo AF: 0.141

Asia WGS AF: 0.107 AC: 375 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fibrous dysplasia of jaw (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.60
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28516876; hg19: chr4-2829409;