12-111418767-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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:3

Conservation

PhyloP100: 6.24

Publications

30 publications found

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 Gene-Disease associations (from GenCC):

acute lymphoblastic leukemia
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
growth retardation-mild developmental delay-chronic hepatitis syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
primary familial polycythemia due to EPO receptor mutation
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
thrombocythemia 1
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

SH2B3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 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 VariationId is 30445.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000763 (116/152086) while in subpopulation AMR AF = 0.00222 (34/15288). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3 link	c.622G>C	p.Glu208Gln	missense_variant	Exon 2 of 8	ENST00000341259.7	NP_005466.1	Q9UQQ2Q59H48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B3	ENST00000341259.7 link	c.622G>C	p.Glu208Gln	missense_variant	Exon 2 of 8	1	NM_005475.3	ENSP00000345492.2		Q9UQQ2
SH2B3	ENST00000550925.2 link	c.427G>C	p.Glu143Gln	missense_variant	Exon 1 of 2	5		ENSP00000473529.1		R4GN84

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

GnomAD2 exomes

AF:

0.00109

AC:

AN:

77392

AF XY:

0.00101

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 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

African (AFR)

AF:

0.000268

AC:

AN:

26158

American (AMR)

AF:

0.00234

AC:

AN:

26954

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

22860

East Asian (EAS)

AF:

0.00

AC:

AN:

29372

South Asian (SAS)

AF:

0.000380

AC:

AN:

73758

European-Finnish (FIN)

AF:

0.0000298

AC:

AN:

33534

Middle Eastern (MID)

AF:

0.0166

AC:

AN:

3922

European-Non Finnish (NFE)

AF:

0.000546

AC:

576

AN:

1055104

Other (OTH)

AF:

0.00151

AC:

AN:

54830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000763

AC:

116

AN:

152086

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41520

American (AMR)

AF:

0.00222

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0377

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000721

AC:

AN:

67936

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 05, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Thrombocythemia 1

Pathogenic:1Benign:1

Aug 12, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 10, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hepatoblastoma

Uncertain:1

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Primary myelofibrosis

Benign:1

Aug 27, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1-supp, PP3 -

Hereditary cancer

Benign:1

Sep 11, 2024

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

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

(source)

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

PhyloP100

6.2

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

PromoterAI

0.040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.40

Mutation Taster

=23/77

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over