Variant 12-111418377-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_005475.3(SH2B3):c.232G>A(p.Glu78Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,516,032 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 8.58

Variant links:

Genes affected

SH2B3 (HGNC:29605): (SH2B adaptor protein 3) This gene encodes a member of the SH2B adaptor family of proteins, which are involved in a range of signaling activities by growth factor and cytokine receptors. The encoded protein is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. Mutations in this gene have been associated with susceptibility to celiac disease type 13 and susceptibility to insulin-dependent diabetes mellitus. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

SH2B3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07305518).

BP6

Variant 12-111418377-G-A is Benign according to our data. Variant chr12-111418377-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3050076.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B3	NM_005475.3 linkuse as main transcript	c.232G>A	p.Glu78Lys	missense_variant	2/8	ENST00000341259.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B3	ENST00000341259.7 linkuse as main transcript	c.232G>A	p.Glu78Lys	missense_variant	2/8	1	NM_005475.3	P1
SH2B3	ENST00000550925.2 linkuse as main transcript	c.40G>A	p.Glu14Lys	missense_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.000837

AC:

127

AN:

151770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00306

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00103

AC:

121

AN:

117196

Hom.:

AF XY:

0.00108

AC XY:

AN XY:

64946

show subpopulations

Gnomad AFR exome

AF:

0.000625

Gnomad AMR exome

AF:

0.000131

Gnomad ASJ exome

AF:

0.00223

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00590

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.000838

GnomAD4 exome

AF:

0.00113

AC:

1536

AN:

1364262

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

761

AN XY:

673514

show subpopulations

Gnomad4 AFR exome

AF:

0.000104

Gnomad4 AMR exome

AF:

0.000203

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00508

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.000837

AC:

127

AN:

151770

Hom.:

Cov.:

AF XY:

0.000836

AC XY:

AN XY:

74130

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00306

Gnomad4 NFE

AF:

0.00128

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.000586

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.000703

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

SH2B3-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.33

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Benign

0.17

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.073

MetaSVM

Benign

-0.98

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.25

Sift

Uncertain

0.016

Sift4G

Benign

0.070

Polyphen

0.90

Vest4

0.75

MVP

0.89

MPC

1.4

ClinPred

0.051

GERP RS

2.1

Varity_R

0.42

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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