12-111418201-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005475.3(SH2B3):​c.56C>G​(p.Pro19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P19P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SH2B3
NM_005475.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.463
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]

Genome browser will be placed here

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=0.09693369).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SH2B3NM_005475.3 linkc.56C>G p.Pro19Arg 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
SH2B3ENST00000341259.7 linkc.56C>G p.Pro19Arg missense_variant Exon 2 of 8 1 NM_005475.3 ENSP00000345492.2 Q9UQQ2
SH2B3ENST00000550925.2 linkc.-140C>G upstream_gene_variant 5 ENSP00000473529.1 R4GN84

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152176
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000494
AC:
1
AN:
202376
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
113634
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:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1423364
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
708152
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:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152294
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000866
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 03, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P19R variant (also known as c.56C>G), located in coding exon 1 of the SH2B3 gene, results from a C to G substitution at nucleotide position 56. The proline at codon 19 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
0.11
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
14
DANN
Benign
0.70
DEOGEN2
Uncertain
0.44
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.29
T
M_CAP
Benign
0.0027
T
MetaRNN
Benign
0.097
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-2.1
N
REVEL
Benign
0.031
Sift
Benign
0.070
T
Sift4G
Uncertain
0.0040
D
Polyphen
0.0
B
Vest4
0.084
MutPred
0.16
Loss of loop (P = 0.0031);
MVP
0.39
MPC
0.79
ClinPred
0.042
T
GERP RS
0.47
Varity_R
0.059
gMVP
0.18

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.

Other links and lift over

dbSNP: rs778291950; hg19: chr12-111856005; API