12-111446804-T-C

Position:

chr12-111446804-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005475.3(SH2B3):c.784T>C(p.Trp262Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,570,508 control chromosomes in the GnomAD database, including 282,793 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.68 ( 37727 hom., cov: 32)

Exomes 𝑓: 0.57 ( 245066 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.878

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:

ATXN2 (HGNC:10555): (ataxin 2) This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ATXN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2047894E-6).

BP6

Variant 12-111446804-T-C is Benign according to our data. Variant chr12-111446804-T-C is described in ClinVar as [Benign]. Clinvar id is 1265448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH2B3	NM_005475.3 linkuse as main transcript	c.784T>C	p.Trp262Arg	missense_variant	3/8	ENST00000341259.7	NP_005466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SH2B3	ENST00000341259.7 linkuse as main transcript	c.784T>C	p.Trp262Arg	missense_variant	3/8	1	NM_005475.3	ENSP00000345492	P1
SH2B3	ENST00000538307.1 linkuse as main transcript	c.178T>C	p.Trp60Arg	missense_variant	2/7	2		ENSP00000440597
ATXN2	ENST00000642389.2 linkuse as main transcript	c.*171-2617A>G		intron_variant, NMD_transcript_variant				ENSP00000496055

Frequencies

GnomAD3 genomes

AF:

0.676

AC:

102715

AN:

151964

Hom.:

37652

Cov.:

show subpopulations

Gnomad AFR

AF:

0.918

Gnomad AMI

AF:

0.543

Gnomad AMR

AF:

0.706

Gnomad ASJ

AF:

0.330

Gnomad EAS

AF:

0.998

Gnomad SAS

AF:

0.905

Gnomad FIN

AF:

0.602

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.513

Gnomad OTH

AF:

0.647

GnomAD3 exomes

AF:

0.667

AC:

147137

AN:

220466

Hom.:

53297

AF XY:

0.661

AC XY:

77382

AN XY:

117014

show subpopulations

Gnomad AFR exome

AF:

0.931

Gnomad AMR exome

AF:

0.789

Gnomad ASJ exome

AF:

0.341

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.898

Gnomad FIN exome

AF:

0.603

Gnomad NFE exome

AF:

0.511

Gnomad OTH exome

AF:

0.601

GnomAD4 exome

AF:

0.571

AC:

809276

AN:

1418426

Hom.:

245066

Cov.:

AF XY:

0.577

AC XY:

403420

AN XY:

699524

show subpopulations

Gnomad4 AFR exome

AF:

0.935

Gnomad4 AMR exome

AF:

0.774

Gnomad4 ASJ exome

AF:

0.349

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.892

Gnomad4 FIN exome

AF:

0.599

Gnomad4 NFE exome

AF:

0.514

Gnomad4 OTH exome

AF:

0.598

GnomAD4 genome

AF:

0.676

AC:

102854

AN:

152082

Hom.:

37727

Cov.:

AF XY:

0.688

AC XY:

51173

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.918

Gnomad4 AMR

AF:

0.707

Gnomad4 ASJ

AF:

0.330

Gnomad4 EAS

AF:

0.998

Gnomad4 SAS

AF:

0.905

Gnomad4 FIN

AF:

0.602

Gnomad4 NFE

AF:

0.513

Gnomad4 OTH

AF:

0.650

Alfa

AF:

0.544

Hom.:

52514

Bravo

AF:

0.690

TwinsUK

AF:

0.509

AC:

1889

ALSPAC

AF:

0.550

AC:

2118

ESP6500AA

AF:

0.906

AC:

3992

ESP6500EA

AF:

0.495

AC:

4254

ExAC

AF:

0.662

AC:

79944

Asia WGS

AF:

0.943

AC:

3277

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	This variant is associated with the following publications: (PMID: 26553438, 28628107, 29547645, 21909115, 26621817, 18311140, 20546165, 23222517, 24777453, 19820697, 19198610, 17554260, 24026423, 24482502, 20560212) -

Primary myelofibrosis;C3277671:Thrombocythemia 1;C4551637:Primary familial polycythemia due to EPO receptor mutation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.24

DEOGEN2

Benign

0.25

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.0068

T;T

MetaRNN

Benign

0.0000012

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.3

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

4.2

N;N

REVEL

Benign

0.16

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.040

MutPred

0.15

Gain of disorder (P = 0.0048);.;

MPC

0.11

ClinPred

0.0019

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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