Genetic Variant SH2B3:p.Pro23Arg (chr12-111418213-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting

The NM_005475.3(SH2B3):c.68C>G(p.Pro23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000063 in 1,428,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36667922).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000063 (9/1428218) while in subpopulation MID AF= 0.00138 (6/4346). AF 95% confidence interval is 0.0006. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3 link	c.68C>G	p.Pro23Arg	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.68C>G	p.Pro23Arg	missense_variant	Exon 2 of 8	1	NM_005475.3	ENSP00000345492.2		Q9UQQ2
SH2B3	ENST00000550925.2 link	c.-128C>G		upstream_gene_variant		5		ENSP00000473529.1		R4GN84

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000196

AC:

AN:

204280

Hom.:

AF XY:

0.0000174

AC XY:

AN XY:

114650

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000106

Gnomad OTH exome

AF:

0.000590

GnomAD4 exome

AF:

0.00000630

AC:

AN:

1428218

Hom.:

Cov.:

AF XY:

0.00000563

AC XY:

AN XY:

710640

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000506

GnomAD4 genome

Cov.:

Alfa

AF:

0.000204

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000262

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P23R variant (also known as c.68C>G), located in coding exon 1 of the SH2B3 gene, results from a C to G substitution at nucleotide position 68. The proline at codon 23 is replaced by arginine, an amino acid with dissimilar 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

0.21

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.65

Eigen

Benign

-0.016

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.69

M_CAP

Benign

0.013

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.7

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.076

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.010

Polyphen

0.97

Vest4

0.29

MutPred

0.17

Gain of MoRF binding (P = 0.0167);

MVP

0.82

MPC

0.79

ClinPred

0.30

GERP RS

3.7

Varity_R

0.21

gMVP

0.40

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