Genetic Variant SH3BP2:p.Ala155Gly (chr4-2827265-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001122681.2(SH3BP2):c.464C>G(p.Ala155Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. A155T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

SH3BP2
NM_001122681.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.25

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33969215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SH3BP2	NM_001122681.2 link	c.464C>G	p.Ala155Gly	missense_variant	Exon 6 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2 link	c.635C>G	p.Ala212Gly	missense_variant	Exon 6 of 13		NP_001139328.1
SH3BP2	NM_001145855.2 link	c.548C>G	p.Ala183Gly	missense_variant	Exon 6 of 13		NP_001139327.1
SH3BP2	NM_003023.4 link	c.464C>G	p.Ala155Gly	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>G	p.Ala155Gly	missense_variant	Exon 6 of 13	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

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

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.34

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

MetaSVM

Uncertain

0.014

MutationAssessor

Benign

1.9

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

PhyloP100

3.3

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.095

Sift

Uncertain

0.021

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

Sift4G

Benign

0.14

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

Polyphen

0.46

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

Vest4

0.28

MutPred

0.20

Loss of catalytic residue at A155 (P = 0.0592);Loss of catalytic residue at A155 (P = 0.0592);Loss of catalytic residue at A155 (P = 0.0592);Loss of catalytic residue at A155 (P = 0.0592);.;Loss of catalytic residue at A155 (P = 0.0592);Loss of catalytic residue at A155 (P = 0.0592);.;Loss of catalytic residue at A155 (P = 0.0592);

MVP

0.90

MPC

0.49

ClinPred

0.46

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

Mutation Taster

=92/8

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over