4-2829656-T-G

Variant names:

• chr4-2829656-T-G
• rs231399
• NM_001122681.2:c.750T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001122681.2(SH3BP2):​c.750T>G​(p.Ala250Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,611,582 control chromosomes in the GnomAD database, including 200,283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A250A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.47 (17057 hom., cov: 29)
  • Exomes 𝑓: 0.50 (183226 hom.)
• Consequence: SH3BP2 NM_001122681.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.742
• Publications: 25 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), Orphanet, G2P, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-2829656-T-G is Benign according to our data. Variant chr4-2829656-T-G is described in ClinVar as Benign. ClinVar VariationId is 258898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.742 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.567 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	NM_001122681.2	MANE Select	c.750T>G	p.Ala250Ala	synonymous	Exon 8 of 13	NP_001116153.1	A0A384N6E5
	SH3BP2	NM_001145856.2		c.921T>G	p.Ala307Ala	synonymous	Exon 8 of 13	NP_001139328.1	P78314-4
	SH3BP2	NM_001145855.2		c.834T>G	p.Ala278Ala	synonymous	Exon 8 of 13	NP_001139327.1	P78314-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.750T>G	p.Ala250Ala	synonymous	Exon 8 of 13	ENSP00000422168.3	P78314-1
	SH3BP2	ENST00000511747.6	TSL:1	c.921T>G	p.Ala307Ala	synonymous	Exon 8 of 13	ENSP00000424846.2	P78314-4
	SH3BP2	ENST00000356331.10	TSL:1	n.1011T>G		non_coding_transcript_exon	Exon 8 of 13

Frequencies

GnomAD3 genomes AF: 0.470 AC: 70975 AN: 151152 Hom.: 17042 Cov.: 29

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.491

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.475

GnomAD2 exomes AF: 0.509 AC: 127187 AN: 250048 AF XY: 0.509

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.642

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.494

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.499 AC: 728086 AN: 1460314 Hom.: 183226 Cov.: 50 AF XY: 0.500 AC XY: 363530 AN XY: 726488

African (AFR) AF: 0.371 AC: 12432 AN: 33468

American (AMR) AF: 0.635 AC: 28399 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 12722 AN: 26116

East Asian (EAS) AF: 0.461 AC: 18300 AN: 39698

South Asian (SAS) AF: 0.564 AC: 48652 AN: 86240

European-Finnish (FIN) AF: 0.462 AC: 24312 AN: 52598

Middle Eastern (MID) AF: 0.517 AC: 2978 AN: 5764

European-Non Finnish (NFE) AF: 0.495 AC: 550238 AN: 1111362

Other (OTH) AF: 0.498 AC: 30053 AN: 60360

GnomAD4 genome AF: 0.470 AC: 71021 AN: 151268 Hom.: 17057 Cov.: 29 AF XY: 0.473 AC XY: 34933 AN XY: 73864

African (AFR) AF: 0.376 AC: 15498 AN: 41194

American (AMR) AF: 0.577 AC: 8782 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 1700 AN: 3464

East Asian (EAS) AF: 0.469 AC: 2378 AN: 5068

South Asian (SAS) AF: 0.558 AC: 2665 AN: 4772

European-Finnish (FIN) AF: 0.454 AC: 4752 AN: 10472

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33518 AN: 67782

Other (OTH) AF: 0.478 AC: 1005 AN: 2102

Alfa AF: 0.487 Hom.: 69013

Bravo AF: 0.475

Asia WGS AF: 0.528 AC: 1835 AN: 3478

EpiCase AF: 0.496

EpiControl AF: 0.492

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Fibrous dysplasia of jaw (5)
-	-	3	not specified (3)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.35
PhyloP100		-0.74
PromoterAI		0.0036	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs231399; hg19: chr4-2831383; COSMIC: COSV62553745; COSMIC: COSV62553745;