12-111418609-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005475.3(SH2B3):c.464C>T(p.Pro155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,489,000 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 1 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.31

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008155733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B3	NM_005475.3 linkuse as main transcript	c.464C>T	p.Pro155Leu	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.464C>T	p.Pro155Leu	missense_variant	2/8	1	NM_005475.3	P1
SH2B3	ENST00000550925.2 linkuse as main transcript	c.272C>T	p.Pro91Leu	missense_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

151766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000853

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000486

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000320

AC:

AN:

118718

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

68010

show subpopulations

Gnomad AFR exome

AF:

0.000251

Gnomad AMR exome

AF:

0.000695

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.000297

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000537

AC:

718

AN:

1337126

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

331

AN XY:

662498

show subpopulations

Gnomad4 AFR exome

AF:

0.0000747

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000340

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000530

Gnomad4 NFE exome

AF:

0.000599

Gnomad4 OTH exome

AF:

0.000549

GnomAD4 genome

AF:

0.000362

AC:

AN:

151874

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000852

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000191

Gnomad4 NFE

AF:

0.000486

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000265

Hom.:

Bravo

AF:

0.000366

ExAC

AF:

0.000263

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 30, 2021

This sequence change has been previously described in a patient with overhydrated stomatocytes and was classified as a variant of unknown significance (PMID: 31298594). This sequence change has been described in the gnomAD database with a low population frequency of 0.033% (dbSNP rs531156627). The p.Pro155Leu change affects a highly conserved amino acid residue located in a domain of the SH2B3 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro155Leu substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro155Leu change remains unknown at this time. -

Thrombocythemia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Dec 14, 2022

This SH2B3 missense variant has been reported in two individuals, one with idiopathic erythrocytosis, and the other with overhydrated stomatocytosis. c.464C>T (rs531156627) has an entry in ClinVar4 (Variation ID 1336169), and is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 55/151766 total alleles; 0.036%; no homozygotes). Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be tolerated, and the proline residue at this position is evolutionarily conserved across many of the species assessed. We consider the clinical significance of c.464C>T; p.Pro155Leu in SH2B3 to be uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.50

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.0082

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.040

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.014

Polyphen

0.46

Vest4

0.31

MVP

0.75

MPC

1.1

ClinPred

0.070

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.15

gMVP

0.38

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