4-2820625-C-T

Position:

• chr4-2820625-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000503393.8(SH3BP2):​c.8C>T​(p.Ala3Val) variant causes a missense change. 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: 34)
• Consequence: SH3BP2 ENST00000503393.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24749789).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.8C>T	p.Ala3Val	missense_variant	2/13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.179C>T	p.Ala60Val	missense_variant	2/13		NP_001139328.1
SH3BP2	NM_001145855.2	c.92C>T	p.Ala31Val	missense_variant	2/13		NP_001139327.1
SH3BP2	NM_003023.4	c.8C>T	p.Ala3Val	missense_variant	2/13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.8C>T	p.Ala3Val	missense_variant	2/13	1	NM_001122681.2	ENSP00000422168	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fibrous dysplasia of jaw Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 21, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SH3BP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3 of the SH3BP2 protein (p.Ala3Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.;T;T;.;.;.;T;T;.;T
Eigen	Benign	0.041
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	.;.;D;D;D;D;D;D;.;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.048	T
MutationAssessor	Benign	0.55	N;.;.;.;.;.;.;.;N;N;.;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.86	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.089
Sift	Uncertain	0.028	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D;D;T;D;D;D;D;D;D
Polyphen		0.86	P;.;.;.;.;.;.;.;P;P;.;P
Vest4		0.28
MutPred		0.23		Gain of catalytic residue at A3 (P = 0.0255);Gain of catalytic residue at A3 (P = 0.0255);Gain of catalytic residue at A3 (P = 0.0255);Gain of catalytic residue at A3 (P = 0.0255);Gain of catalytic residue at A3 (P = 0.0255);Gain of catalytic residue at A3 (P = 0.0255);.;Gain of catalytic residue at A3 (P = 0.0255);Gain of catalytic residue at A3 (P = 0.0255);Gain of catalytic residue at A3 (P = 0.0255);.;Gain of catalytic residue at A3 (P = 0.0255);
MVP		0.88
MPC		0.51
ClinPred		0.64	D
GERP RS		5.0
Varity_R		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-2822352;