Genetic Variant SH2B3:p.Ser9Pro (chr12-111418170-T-C) – ACMG Classification: Likely_benign (-2 pts)

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>C(p.Ser9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S9A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.19

Publications

0 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:

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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=0.05645722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3 link	c.25T>C	p.Ser9Pro	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.25T>C	p.Ser9Pro	missense_variant	Exon 2 of 8	1	NM_005475.3	ENSP00000345492.2		Q9UQQ2
SH2B3	ENST00000550925.2 link	c.-171T>C		upstream_gene_variant		5		ENSP00000473529.1		R4GN84

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1397578

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693752

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:

0.00

AC:

AN:

1093518

Other (OTH)

AF:

0.00

AC:

AN:

58268

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 27, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S9P variant (also known as c.25T>C), located in coding exon 1 of the SH2B3 gene, results from a T to C substitution at nucleotide position 25. The serine at codon 9 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

6.7

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.25

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.33

M_CAP

Benign

0.0065

MetaRNN

Benign

0.056

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

-1.2

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.95

REVEL

Benign

0.038

Sift

Benign

0.096

Sift4G

Benign

0.25

Polyphen

0.0010

Vest4

0.052

MutPred

0.097

Loss of phosphorylation at S9 (P = 0.0089);

MVP

0.43

MPC

0.94

ClinPred

0.024

GERP RS

0.97

PromoterAI

-0.070

Neutral

(source)

Varity_R

0.12

gMVP

0.29

Mutation Taster

=91/9

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over