4-2829656-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.742

Publications

25 publications found

Variant links:

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

SH3BP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SH3BP2	NM_001122681.2 link	c.750T>G	p.Ala250Ala	synonymous_variant	Exon 8 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2 link	c.921T>G	p.Ala307Ala	synonymous_variant	Exon 8 of 13		NP_001139328.1
SH3BP2	NM_001145855.2 link	c.834T>G	p.Ala278Ala	synonymous_variant	Exon 8 of 13		NP_001139327.1
SH3BP2	NM_003023.4 link	c.750T>G	p.Ala250Ala	synonymous_variant	Exon 8 of 13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8 link	c.750T>G	p.Ala250Ala	synonymous_variant	Exon 8 of 13	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes

AF:

0.470

AC:

70975

AN:

151152

Hom.:

17042

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.500

AC XY:

363530

AN XY:

726488

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

20137

40274

60411

80548

100685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16112

32224

48336

64448

80560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.470

AC:

71021

AN:

151268

Hom.:

17057

Cov.:

AF XY:

0.473

AC XY:

34933

AN XY:

73864

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

1876

3752

5627

7503

9379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

656

1312

1968

2624

3280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fibrous dysplasia of jaw

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 82. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.3

(source)

DANN

Benign

0.35

PhyloP100

-0.74

PromoterAI

0.0036

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over