12-111418869-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005475.3(SH2B3):c.724C>T(p.Pro242Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,410,322 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0019 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 21 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.88

Publications

21 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0091224015).

BP6

Variant 12-111418869-C-T is Benign according to our data. Variant chr12-111418869-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3766887.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

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.724C>T	p.Pro242Ser	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.724C>T	p.Pro242Ser	missense	Exon 2 of 8	ENSP00000345492.2	Q9UQQ2
SH2B3	ENST00000896496.1		c.724C>T	p.Pro242Ser	missense	Exon 2 of 8	ENSP00000566555.1
SH2B3	ENST00000935782.1		c.724C>T	p.Pro242Ser	missense	Exon 2 of 8	ENSP00000605841.1

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

295

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0552

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00275

AC:

AN:

15638

AF XY:

0.00303

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0493

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000955

AC:

1201

AN:

1257976

Hom.:

Cov.:

AF XY:

0.000895

AC XY:

551

AN XY:

615644

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24058

American (AMR)

AF:

0.00

AC:

AN:

13244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18152

East Asian (EAS)

AF:

0.0400

AC:

1122

AN:

28064

South Asian (SAS)

AF:

0.000182

AC:

AN:

60576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30342

Middle Eastern (MID)

AF:

0.000556

AC:

AN:

3594

European-Non Finnish (NFE)

AF:

0.0000146

AC:

AN:

1027930

Other (OTH)

AF:

0.000980

AC:

AN:

52016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

126

189

252

315

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:

0.00194

AC:

295

AN:

152346

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

162

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41582

American (AMR)

AF:

0.000261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.0553

AC:

287

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00140

Hom.:

Bravo

AF:

0.00323

ExAC

AF:

0.000275

AC:

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0091

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PhyloP100

6.9

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.9

REVEL

Benign

0.23

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.040

Polyphen

0.99

Vest4

0.56

MVP

0.92

MPC

0.34

ClinPred

0.20

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.69

Mutation Taster

=83/17

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

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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