4-2820651-A-T

Variant names:

• chr4-2820651-A-T
• rs148117486
• NM_001122681.2:c.34A>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	NM_001122681.2	MANE Select	c.34A>T	p.Met12Leu	missense	Exon 2 of 13	NP_001116153.1
	SH3BP2	NM_001145856.2		c.205A>T	p.Met69Leu	missense	Exon 2 of 13	NP_001139328.1
	SH3BP2	NM_001145855.2		c.118A>T	p.Met40Leu	missense	Exon 2 of 13	NP_001139327.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.34A>T	p.Met12Leu	missense	Exon 2 of 13	ENSP00000422168.3
	SH3BP2	ENST00000511747.6	TSL:1	c.205A>T	p.Met69Leu	missense	Exon 2 of 13	ENSP00000424846.2
	SH3BP2	ENST00000356331.10	TSL:1	n.295A>T		non_coding_transcript_exon	Exon 2 of 13

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.1	L
PhyloP100		8.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.29
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.73	P
Vest4		0.58
MutPred		0.49		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
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs148117486; hg19: chr4-2822378;