Genetic Variant SH3BP2:p.Ser4Ala (chr4-2818233-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001122681.2(SH3BP2):c.-4-2381T>G variant causes a intron 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SH3BP2
NM_001122681.2 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.58

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034372687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2 link	c.-4-2381T>G		intron_variant	Intron 1 of 12	ENST00000503393.8	NP_001116153.1	P78314-1A0A384N6E5
SH3BP2	NM_001145856.2 link	c.10T>G	p.Ser4Ala	missense_variant	Exon 1 of 13		NP_001139328.1	P78314-4
SH3BP2	NM_001145855.2 link	c.81-2381T>G		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.-4-2381T>G		intron_variant	Intron 1 of 12	1	NM_001122681.2	ENSP00000422168.3		P78314-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

839492

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

388416

African (AFR)

AF:

0.00

AC:

AN:

15898

American (AMR)

AF:

0.00

AC:

AN:

1250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5284

East Asian (EAS)

AF:

0.00

AC:

AN:

3862

South Asian (SAS)

AF:

0.00

AC:

AN:

17222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1632

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

765726

Other (OTH)

AF:

0.00

AC:

AN:

27690

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.10T>G (p.S4A) alteration is located in exon 1 (coding exon 1) of the SH3BP2 gene. This alteration results from a T to G substitution at nucleotide position 10, causing the serine (S) at amino acid position 4 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.1

(source)

DANN

Benign

0.85

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.15

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.93

PhyloP100

-2.6

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.13

REVEL

Benign

0.22

Sift

Benign

1.0

Vest4

0.083

MutPred

0.20

Loss of phosphorylation at S4 (P = 0.0014);

MVP

0.27

MPC

0.13

ClinPred

0.038

GERP RS

-1.1

PromoterAI

0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=293/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over