4-2818312-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The ENST00000511747.6(SH3BP2):c.89C>T(p.Pro30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,105,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

SH3BP2
ENST00000511747.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.66

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11494297).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000189 (28/147956) while in subpopulation AMR AF= 0.000402 (6/14940). AF 95% confidence interval is 0.000174. There are 0 homozygotes in gnomad4. There are 13 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 GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SH3BP2	NM_001122681.2 linkuse as main transcript	c.-4-2302C>T		intron_variant		ENST00000503393.8
SH3BP2	NM_001145856.2 linkuse as main transcript	c.89C>T	p.Pro30Leu	missense_variant	1/13
SH3BP2	NM_001145855.2 linkuse as main transcript	c.81-2302C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8 linkuse as main transcript	c.-4-2302C>T		intron_variant		1	NM_001122681.2	P2	P78314-1

Frequencies

GnomAD3 genomes

AF:

0.000189

AC:

AN:

147856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000402

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:

0.000226

Gnomad OTH

AF:

0.000985

GnomAD4 exome

AF:

0.000180

AC:

172

AN:

957126

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

AN XY:

448892

show subpopulations

Gnomad4 AFR exome

AF:

0.000160

Gnomad4 AMR exome

AF:

0.000889

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000185

Gnomad4 OTH exome

AF:

0.000257

GnomAD4 genome

AF:

0.000189

AC:

AN:

147956

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

72116

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.000402

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000226

Gnomad4 OTH

AF:

0.000975

Alfa

AF:

0.000569

Hom.:

Bravo

AF:

0.000325

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

Feb 05, 2024

The c.89C>T (p.P30L) alteration is located in exon 1 (coding exon 1) of the SH3BP2 gene. This alteration results from a C to T substitution at nucleotide position 89, causing the proline (P) at amino acid position 30 to be replaced by a leucine (L). 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

-0.21

BayesDel_noAF

Benign

-0.54

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.32

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.87

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.87

REVEL

Benign

0.21

Sift

Benign

0.032

Vest4

0.11

MutPred

0.21

Gain of MoRF binding (P = 0.0366);

MVP

0.31

MPC

0.17

ClinPred

0.24

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

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