4-2827265-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001122681.2(SH3BP2):c.464C>T(p.Ala155Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,614,226 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A155T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0044 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0070 ( 54 hom. )

Consequence

SH3BP2
NM_001122681.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.25

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006905973).

BP6

Variant 4-2827265-C-T is Benign according to our data. Variant chr4-2827265-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 348574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00442 (674/152362) while in subpopulation NFE AF = 0.00753 (512/68038). AF 95% confidence interval is 0.00699. There are 4 homozygotes in GnomAd4. There are 296 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 674 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SH3BP2	NM_001122681.2 link	c.464C>T	p.Ala155Val	missense_variant	Exon 6 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2 link	c.635C>T	p.Ala212Val	missense_variant	Exon 6 of 13		NP_001139328.1
SH3BP2	NM_001145855.2 link	c.548C>T	p.Ala183Val	missense_variant	Exon 6 of 13		NP_001139327.1
SH3BP2	NM_003023.4 link	c.464C>T	p.Ala155Val	missense_variant	Exon 6 of 13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8 link	c.464C>T	p.Ala155Val	missense_variant	Exon 6 of 13	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes

AF:

0.00443

AC:

674

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00752

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00532

AC:

1337

AN:

251428

AF XY:

0.00533

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00896

Gnomad OTH exome

AF:

0.00521

GnomAD4 exome

AF:

0.00702

AC:

10267

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00698

AC XY:

5078

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

33480

American (AMR)

AF:

0.00302

AC:

135

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00509

AC:

133

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00246

AC:

212

AN:

86258

European-Finnish (FIN)

AF:

0.00109

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0142

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00829

AC:

9215

AN:

1111992

Other (OTH)

AF:

0.00636

AC:

384

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

531

1063

1594

2126

2657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

338

676

1014

1352

1690

<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:

0.00442

AC:

674

AN:

152362

Hom.:

Cov.:

AF XY:

0.00397

AC XY:

296

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41580

American (AMR)

AF:

0.00314

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00269

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00753

AC:

512

AN:

68038

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00720

Hom.:

Bravo

AF:

0.00456

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00562

AC:

682

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00851

EpiControl

AF:

0.00925

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SH3BP2: BP4, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Fibrous dysplasia of jaw

Benign:2

Feb 02, 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. -

not specified

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.;T;T;.;T;T;.;T

Eigen

Benign

-0.069

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.97

.;D;D;D;D;.;.;D;D

MetaRNN

Benign

0.0069

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.9

L;.;.;.;.;L;L;.;L

PhyloP100

3.3

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.0

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.092

Sift

Uncertain

0.0090

D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.18

T;D;D;D;T;T;T;T;T

Polyphen

0.46

P;.;.;.;.;P;P;.;P

Vest4

0.21

MVP

0.90

MPC

0.18

ClinPred

0.011

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.064

Mutation Taster

=98/2

polymorphism

(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