Variant chr4-2818299-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The ENST00000503393.8(SH3BP2):c.-4-2315G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,069,268 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SH3BP2
ENST00000503393.8 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00600

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.061558843).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00171 (252/147416) while in subpopulation AFR AF= 0.00571 (234/40978). AF 95% confidence interval is 0.00511. There are 1 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 252 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SH3BP2	NM_001122681.2 linkuse as main transcript	c.-4-2315G>A		intron_variant		ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2 linkuse as main transcript	c.76G>A	p.Gly26Arg	missense_variant	1/13		NP_001139328.1
SH3BP2	NM_001145855.2 linkuse as main transcript	c.81-2315G>A		intron_variant			NP_001139327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8 linkuse as main transcript	c.-4-2315G>A		intron_variant		1	NM_001122681.2	ENSP00000422168	P2	P78314-1

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

247

AN:

147314

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00560

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000876

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00197

GnomAD4 exome

AF:

0.000142

AC:

131

AN:

921852

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

431342

show subpopulations

Gnomad4 AFR exome

AF:

0.00639

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000555

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000487

GnomAD4 genome

AF:

0.00171

AC:

252

AN:

147416

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

114

AN XY:

71794

show subpopulations

Gnomad4 AFR

AF:

0.00571

Gnomad4 AMR

AF:

0.000874

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000151

Gnomad4 OTH

AF:

0.00195

Alfa

AF:

0.00169

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.76G>A (p.G26R) alteration is located in exon 1 (coding exon 1) of the SH3BP2 gene. This alteration results from a G to A substitution at nucleotide position 76, causing the glycine (G) at amino acid position 26 to be replaced by an arginine (R). 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

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.32

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.82

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.12

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Vest4

0.12

MutPred

0.18

Gain of methylation at G26 (P = 0.0095);

MVP

0.74

MPC

0.19

ClinPred

0.48

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over