12-111418191-T-C

Variant names:

• chr12-111418191-T-C
• NM_005475.3:c.46T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005475.3(SH2B3):​c.46T>C​(p.Ser16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,418,960 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. S16L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SH2B3 NM_005475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.03
• Publications: 0 publications found

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)

ACMG classification

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=0.05555296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3	c.46T>C	p.Ser16Pro	missense_variant	Exon 2 of 8	ENST00000341259.7	NP_005466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B3	ENST00000341259.7	c.46T>C	p.Ser16Pro	missense_variant	Exon 2 of 8	1	NM_005475.3	ENSP00000345492.2
SH2B3	ENST00000550925.2	c.-150T>C		upstream_gene_variant		5		ENSP00000473529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1418960 Hom.: 0 Cov.: 32 AF XY: 0.00000283 AC XY: 2 AN XY: 705650

African (AFR) AF: 0.00 AC: 0 AN: 30842

American (AMR) AF: 0.00 AC: 0 AN: 40366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24586

East Asian (EAS) AF: 0.00 AC: 0 AN: 38294

South Asian (SAS) AF: 0.00 AC: 0 AN: 81826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4200

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1101916

Other (OTH) AF: 0.0000169 AC: 1 AN: 59050

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S16P variant (also known as c.46T>C), located in coding exon 1 of the SH2B3 gene, results from a T to C substitution at nucleotide position 46. The serine at codon 16 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	0.060
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.2
DANN	Benign	0.44
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
PhyloP100		-1.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.019
Sift	Benign	0.24	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.17		Loss of phosphorylation at S16 (P = 0.0068);
MVP		0.25
MPC		0.94
ClinPred		0.070	T
GERP RS		-3.8
PromoterAI		-0.061	Neutral
Varity_R		0.053
gMVP		0.19
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

hg19: chr12-111855995;