12-111418767-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_005475.3(SH2B3):c.622G>C(p.Glu208Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000663 in 1,478,578 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 3 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:2

Conservation

PhyloP100: 6.24

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03058815).

BP6

Variant 12-111418767-G-C is Benign according to our data. Variant chr12-111418767-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30445.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B3	NM_005475.3 linkuse as main transcript	c.622G>C	p.Glu208Gln	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.622G>C	p.Glu208Gln	missense_variant	2/8	1	NM_005475.3	P1
SH2B3	ENST00000550925.2 linkuse as main transcript	c.430G>C	p.Glu144Gln	missense_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.000763

AC:

116

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.000721

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00109

AC:

AN:

77392

Hom.:

AF XY:

0.00101

AC XY:

AN XY:

44770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00233

Gnomad ASJ exome

AF:

0.00188

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000303

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000856

Gnomad OTH exome

AF:

0.00396

GnomAD4 exome

AF:

0.000652

AC:

865

AN:

1326492

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

441

AN XY:

654560

show subpopulations

Gnomad4 AFR exome

AF:

0.000268

Gnomad4 AMR exome

AF:

0.00234

Gnomad4 ASJ exome

AF:

0.00184

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000380

Gnomad4 FIN exome

AF:

0.0000298

Gnomad4 NFE exome

AF:

0.000546

Gnomad4 OTH exome

AF:

0.00151

GnomAD4 genome

AF:

0.000763

AC:

116

AN:

152086

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000721

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.000892

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000741

AC:

ExAC

AF:

0.000383

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 05, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Thrombocythemia 1

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 12, 2010	- -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 10, 2023	- -

Developmental and epileptic encephalopathy, 67

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Hepatoblastoma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

- -

Primary myelofibrosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Aug 27, 2021

BS1-supp, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.85

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.2

REVEL

Benign

0.11

Sift

Uncertain

0.022

Sift4G

Uncertain

0.039

Polyphen

1.0

Vest4

0.29

MVP

0.86

MPC

1.5

ClinPred

0.078

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.40

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