Variant 12-111418383-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005475.3(SH2B3):c.238C>T(p.Arg80Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,506,870 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0081 ( 24 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 16 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.34

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007310182).

BP6

Variant 12-111418383-C-T is Benign according to our data. Variant chr12-111418383-C-T is described in ClinVar as [Benign]. Clinvar id is 3352709.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00815 (1237/151810) while in subpopulation AFR AF= 0.0282 (1170/41520). AF 95% confidence interval is 0.0268. There are 24 homozygotes in gnomad4. There are 592 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B3	NM_005475.3 linkuse as main transcript	c.238C>T	p.Arg80Cys	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.238C>T	p.Arg80Cys	missense_variant	2/8	1	NM_005475.3	P1
SH2B3	ENST00000550925.2 linkuse as main transcript	c.46C>T	p.Arg16Cys	missense_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.00813

AC:

1233

AN:

151702

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0282

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00335

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:

0.0000442

Gnomad OTH

AF:

0.00624

GnomAD3 exomes

AF:

0.00125

AC:

138

AN:

109992

Hom.:

AF XY:

0.000932

AC XY:

AN XY:

61150

show subpopulations

Gnomad AFR exome

AF:

0.0396

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000872

AC:

1182

AN:

1355060

Hom.:

Cov.:

AF XY:

0.000728

AC XY:

487

AN XY:

668668

show subpopulations

Gnomad4 AFR exome

AF:

0.0328

Gnomad4 AMR exome

AF:

0.00183

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000807

Gnomad4 OTH exome

AF:

0.00188

GnomAD4 genome

AF:

0.00815

AC:

1237

AN:

151810

Hom.:

Cov.:

AF XY:

0.00798

AC XY:

592

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.0282

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00618

Alfa

AF:

0.00362

Hom.:

ESP6500AA

AF:

0.0196

AC:

ESP6500EA

AF:

0.000877

AC:

ExAC

AF:

0.00126

AC:

Asia WGS

AF:

0.00265

AC:

AN:

3410

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SH2B3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 16, 2024

This variant is classified as 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

Uncertain

0.55

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Benign

0.13

Eigen_PC

Benign

0.032

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0073

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.14

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.22

MVP

0.75

MPC

2.0

ClinPred

0.031

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.29

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