12-111418164-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005475.3(SH2B3):​c.19C>A​(p.Gln7Lys) 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. 14/22 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: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SH2B3
NM_005475.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.16

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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27656984).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SH2B3NM_005475.3 linkc.19C>A p.Gln7Lys 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.19C>A p.Gln7Lys missense_variant Exon 2 of 8 1 NM_005475.3 ENSP00000345492.2 Q9UQQ2
SH2B3ENST00000550925.2 linkc.-177C>A upstream_gene_variant 5 ENSP00000473529.1 R4GN84

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1383618
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
685794
African (AFR)
AF:
0.00
AC:
0
AN:
29156
American (AMR)
AF:
0.00
AC:
0
AN:
34192
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
22148
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36914
South Asian (SAS)
AF:
0.00
AC:
0
AN:
75246
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
36666
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3952
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1087636
Other (OTH)
AF:
0.00
AC:
0
AN:
57708
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 17, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Q7K variant (also known as c.19C>A), located in coding exon 1 of the SH2B3 gene, results from a C to A substitution at nucleotide position 19. The glutamine at codon 7 is replaced by lysine, 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
0.18
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.27
T
Eigen
Uncertain
0.19
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.55
T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.28
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
L
PhyloP100
3.2
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.86
N
REVEL
Benign
0.088
Sift
Uncertain
0.027
D
Sift4G
Benign
0.49
T
Polyphen
0.90
P
Vest4
0.25
MutPred
0.21
Gain of methylation at Q7 (P = 0.0037);
MVP
0.78
MPC
0.94
ClinPred
0.37
T
GERP RS
4.2
PromoterAI
-0.027
Neutral
Varity_R
0.28
gMVP
0.35
Mutation Taster
=89/11
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

hg19: chr12-111855968; COSMIC: COSV106486928; COSMIC: COSV106486928; API