chr12-111418170-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005475.3(SH2B3):c.25T>G(p.Ser9Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,549,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S9P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.19

Publications

2 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):

syndromic disease
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.037614256).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	NM_005475.3	MANE Select	c.25T>G	p.Ser9Ala	missense	Exon 2 of 8	NP_005466.1	Q9UQQ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.25T>G	p.Ser9Ala	missense	Exon 2 of 8	ENSP00000345492.2	Q9UQQ2
SH2B3	ENST00000896496.1		c.25T>G	p.Ser9Ala	missense	Exon 2 of 8	ENSP00000566555.1
SH2B3	ENST00000935782.1		c.25T>G	p.Ser9Ala	missense	Exon 2 of 8	ENSP00000605841.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183766

AF XY:

0.00000975

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000223

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1397578

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

693752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29986

American (AMR)

AF:

0.00

AC:

AN:

36588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22956

East Asian (EAS)

AF:

0.00

AC:

AN:

37644

South Asian (SAS)

AF:

0.00

AC:

AN:

77504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4020

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

1093518

Other (OTH)

AF:

0.0000343

AC:

AN:

58268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

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:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.74

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.18

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.24

M_CAP

Benign

0.0037

MetaRNN

Benign

0.038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-1.2

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.0

REVEL

Benign

0.019

Sift

Benign

0.33

Sift4G

Benign

0.83

Polyphen

0.0010

Vest4

0.049

MutPred

0.10

Loss of glycosylation at S9 (P = 0.0068)

MVP

0.38

MPC

0.62

ClinPred

0.073

GERP RS

0.97

PromoterAI

0.050

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.043

gMVP

0.19

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over