12-111447506-G-A
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2
The NM_005475.3(SH2B3):c.1198G>A(p.Glu400Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,488,994 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00079 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0015 ( 3 hom. )
Consequence
SH2B3
NM_005475.3 missense
NM_005475.3 missense
Scores
7
6
6
Clinical Significance
Conservation
PhyloP100: 9.60
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]
ATXN2 (HGNC:10555): (ataxin 2) This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.38761103).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00079 (108/136632) while in subpopulation NFE AF= 0.0014 (90/64434). AF 95% confidence interval is 0.00116. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SH2B3 | ENST00000341259.7 | c.1198G>A | p.Glu400Lys | missense_variant | Exon 6 of 8 | 1 | NM_005475.3 | ENSP00000345492.2 | ||
SH2B3 | ENST00000538307.1 | c.592G>A | p.Glu198Lys | missense_variant | Exon 5 of 7 | 2 | ENSP00000440597.1 | |||
ATXN2 | ENST00000642389.2 | n.*171-3319C>T | intron_variant | Intron 26 of 26 | ENSP00000496055.2 |
Frequencies
GnomAD3 genomes AF: 0.000791 AC: 108AN: 136538Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.000582 AC: 144AN: 247234Hom.: 0 AF XY: 0.000581 AC XY: 78AN XY: 134160
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GnomAD4 exome AF: 0.00151 AC: 2042AN: 1352362Hom.: 3 Cov.: 34 AF XY: 0.00148 AC XY: 991AN XY: 669924
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GnomAD4 genome AF: 0.000790 AC: 108AN: 136632Hom.: 0 Cov.: 30 AF XY: 0.000731 AC XY: 47AN XY: 64306
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 04, 2024 | Observed heterozygous in individuals with myelodysplastic syndrome/myeloproliferative neoplasm, juvenile myelomonocytic leukemia, or idiopathic erythrocytosis (PMID: 21990094, 26457647, 27651169, 31173385); Published functional studies demonstrate normal cell growth inhibition (PMID: 21990094); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26607381, 24777453, 27651169, 28484264, 24725463, 31173385, 26457647, 29682367, 33792220, Butler2022[FunctionalStudy], 34662886, 35281324, 35056081, 36324816, 35935937, 38262687, 38417019, 21990094, 33850299, 38862854) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 04, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 01, 2024 | PM1 - |
Primary myelofibrosis;C3277671:Thrombocythemia 1;C4551637:Primary familial polycythemia due to EPO receptor mutation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at