Genetic Variant SH3BP2:p.Arg80Leu (chr4-2823037-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001122681.2(SH3BP2):c.239G>T(p.Arg80Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R80Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

SH3BP2
NM_001122681.2 missense, splice_region

Scores

Splicing: ADA: 0.9989

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.89

Publications

5 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SH3BP2	NM_001122681.2	MANE Select	c.239G>T	p.Arg80Leu	missense splice_region	Exon 3 of 13	NP_001116153.1
SH3BP2	NM_001145856.2		c.410G>T	p.Arg137Leu	missense splice_region	Exon 3 of 13	NP_001139328.1
SH3BP2	NM_001145855.2		c.323G>T	p.Arg108Leu	missense splice_region	Exon 3 of 13	NP_001139327.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.239G>T	p.Arg80Leu	missense splice_region	Exon 3 of 13	ENSP00000422168.3
SH3BP2	ENST00000511747.6	TSL:1	c.410G>T	p.Arg137Leu	missense splice_region	Exon 3 of 13	ENSP00000424846.2
SH3BP2	ENST00000356331.10	TSL:1	n.500G>T		splice_region non_coding_transcript_exon	Exon 3 of 13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

249582

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.5

PhyloP100

5.9

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.63

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0020

Polyphen

0.84

Vest4

0.86

MutPred

0.78

Loss of catalytic residue at R80 (P = 0.0341)

MVP

0.90

MPC

0.54

ClinPred

0.98

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.52

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over