NM_001122681.2:c.1514C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001122681.2(SH3BP2):c.1514C>G(p.Ser505Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,614,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S505F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

SH3BP2
NM_001122681.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.934

Publications

4 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006813228).

BP6

Variant 4-2833015-C-G is Benign according to our data. Variant chr4-2833015-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 348593.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00275 (419/152374) while in subpopulation AFR AF = 0.0088 (366/41584). AF 95% confidence interval is 0.00806. There are 0 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 419 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2 link	c.1514C>G	p.Ser505Cys	missense_variant	Exon 12 of 13	ENST00000503393.8	NP_001116153.1	P78314-1A0A384N6E5
SH3BP2	NM_001145856.2 link	c.1685C>G	p.Ser562Cys	missense_variant	Exon 12 of 13		NP_001139328.1	P78314-4
SH3BP2	NM_001145855.2 link	c.1598C>G	p.Ser533Cys	missense_variant	Exon 12 of 13		NP_001139327.1	P78314-3
SH3BP2	NM_003023.4 link	c.1514C>G	p.Ser505Cys	missense_variant	Exon 12 of 13		NP_003014.3	P78314-1A0A384N6E5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8 link	c.1514C>G	p.Ser505Cys	missense_variant	Exon 12 of 13	1	NM_001122681.2	ENSP00000422168.3		P78314-1

Frequencies

GnomAD3 genomes

AF:

0.00275

AC:

419

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00883

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000668

AC:

168

AN:

251438

AF XY:

0.000508

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000312

AC:

456

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

192

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00983

AC:

329

AN:

33480

American (AMR)

AF:

0.000961

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1112000

Other (OTH)

AF:

0.000878

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00275

AC:

419

AN:

152374

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

184

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00880

AC:

366

AN:

41584

American (AMR)

AF:

0.00274

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68034

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000148

Hom.:

Bravo

AF:

0.00306

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000667

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fibrous dysplasia of jaw

Uncertain:1Benign:2

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SH3BP2 NM_003023 exon 12 p.Ser505Cys (c.1514C>G): This variant has not been reported in the literature but is present in 0.8% (194/24030) of African alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs144577122). This variant is present in ClinVar (Variation ID:348593). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.47

T;.;T;T;.;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.79

.;T;.;.;T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.0068

T;T;T;T;T;T

MetaSVM

Benign

-0.50

PhyloP100

0.93

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

N;N;N;N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.050

D;D;D;D;D;D

Sift4G

Benign

0.13

T;T;T;T;T;T

Polyphen

0.69

P;.;P;P;.;P

Vest4

0.21

MVP

0.89

MPC

0.16

ClinPred

0.015

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.052

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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