chr4-2820651-A-T

Position:

• chr4-2820651-A-T

Variant summary

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

The NM_001122681.2(SH3BP2):​c.34A>T​(p.Met12Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. M12V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SH3BP2 NM_001122681.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.60

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.34A>T	p.Met12Leu	missense_variant	2/13	ENST00000503393.8
SH3BP2	NM_001145856.2	c.205A>T	p.Met69Leu	missense_variant	2/13
SH3BP2	NM_001145855.2	c.118A>T	p.Met40Leu	missense_variant	2/13
SH3BP2	NM_003023.4	c.34A>T	p.Met12Leu	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.34A>T	p.Met12Leu	missense_variant	2/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T;.;.;T;T;.;.;.;T;T;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	.;.;D;D;D;D;D;D;.;.;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.;.;.;L;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.73	P;.;.;.;.;.;.;.;P;P;.;P
Vest4		0.58
MutPred		0.49		Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);.;Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);.;Gain of methylation at K13 (P = 0.0408);
MVP		0.86
MPC		0.65
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.64

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

LitVar

Other links and lift over

dbSNP: rs148117486; hg19: chr4-2822378;