Genetic Variant SH3BP2:p.Gly5Trp (chr4-2818236-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000511747.6(SH3BP2):c.13G>T(p.Gly5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000119 in 840,526 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G5R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000012 ( 0 hom. )

Consequence

SH3BP2
ENST00000511747.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.353

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2 link	c.-4-2378G>T		intron_variant	Intron 1 of 12	ENST00000503393.8	NP_001116153.1	P78314-1A0A384N6E5
SH3BP2	NM_001145856.2 link	c.13G>T	p.Gly5Trp	missense_variant	Exon 1 of 13		NP_001139328.1	P78314-4
SH3BP2	NM_001145855.2 link	c.81-2378G>T		intron_variant	Intron 1 of 12		NP_001139327.1	P78314-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8 link	c.-4-2378G>T		intron_variant	Intron 1 of 12	1	NM_001122681.2	ENSP00000422168.3		P78314-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000119

AC:

AN:

840526

Hom.:

Cov.:

AF XY:

0.00000257

AC XY:

AN XY:

388924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15916

American (AMR)

AF:

0.00

AC:

AN:

1268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5302

East Asian (EAS)

AF:

0.00

AC:

AN:

3898

South Asian (SAS)

AF:

0.0000580

AC:

AN:

17232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1640

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

766536

Other (OTH)

AF:

0.00

AC:

AN:

27728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.93

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.41

M_CAP

Pathogenic

0.94

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-0.36

PhyloP100

0.35

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.010

REVEL

Benign

0.27

Sift

Pathogenic

0.0

Vest4

0.43

MutPred

0.32

Loss of glycosylation at S4 (P = 0.0088);

MVP

0.66

MPC

0.19

ClinPred

0.25

GERP RS

1.5

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=95/5

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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4-2818236-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over