12-111418767-G-T
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2
The NM_005475.3(SH2B3):c.622G>T(p.Glu208*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Affects (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SH2B3
NM_005475.3 stop_gained
NM_005475.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 6.24
Publications
30 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 leukemiaInheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
- growth retardation-mild developmental delay-chronic hepatitis syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- primary familial polycythemia due to EPO receptor mutationInheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
- schizophreniaInheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
- thrombocythemia 1Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1326496Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 654562
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1326496
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
654562
African (AFR)
AF:
AC:
0
AN:
26158
American (AMR)
AF:
AC:
0
AN:
26958
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
22860
East Asian (EAS)
AF:
AC:
0
AN:
29372
South Asian (SAS)
AF:
AC:
0
AN:
73758
European-Finnish (FIN)
AF:
AC:
0
AN:
33534
Middle Eastern (MID)
AF:
AC:
0
AN:
3922
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1055104
Other (OTH)
AF:
AC:
0
AN:
54830
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Affects
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Primary familial polycythemia due to EPO receptor mutation Other:1
Sep 16, 2010
OMIM
Significance:Affects
Review Status:no assertion criteria provided
Collection Method:literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
PhyloP100
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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