rs143916878
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting
The NM_001382567.1(STIM1):c.454G>A(p.Glu152Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000625 in 1,598,928 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00019 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 1 hom. )
Consequence
STIM1
NM_001382567.1 missense
NM_001382567.1 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 9.79
Genes affected
STIM1 (HGNC:11386): (stromal interaction molecule 1) This gene encodes a type 1 transmembrane protein that mediates Ca2+ influx after depletion of intracellular Ca2+ stores by gating of store-operated Ca2+ influx channels (SOCs). It is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocrotical carcinoma, and lung, ovarian, and breast cancer. This gene may play a role in malignancies and disease that involve this region, as well as early hematopoiesis, by mediating attachment to stromal cells. Mutations in this gene are associated with fatal classic Kaposi sarcoma, immunodeficiency due to defects in store-operated calcium entry (SOCE) in fibroblasts, ectodermal dysplasia and tubular aggregate myopathy. This gene is oriented in a head-to-tail configuration with the ribonucleotide reductase 1 gene (RRM1), with the 3' end of this gene situated 1.6 kb from the 5' end of the RRM1 gene. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.037558585).
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00019 (29/152326) while in subpopulation SAS AF= 0.00124 (6/4822). AF 95% confidence interval is 0.000542. There are 1 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STIM1 | NM_001382567.1 | c.454G>A | p.Glu152Lys | missense_variant | 4/13 | ENST00000526596.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STIM1 | ENST00000526596.2 | c.454G>A | p.Glu152Lys | missense_variant | 4/13 | 5 | NM_001382567.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000191 AC: 29AN: 152208Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000115 AC: 26AN: 226676Hom.: 1 AF XY: 0.0000985 AC XY: 12AN XY: 121818
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GnomAD4 exome AF: 0.0000491 AC: 71AN: 1446602Hom.: 1 Cov.: 30 AF XY: 0.0000474 AC XY: 34AN XY: 717816
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GnomAD4 genome ? AF: 0.000190 AC: 29AN: 152326Hom.: 1 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74482
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2022 | Published functional studies demonstrate a damaging effect, as the E152K variant in the heterozygous form deregulates Ca2+ signaling, increasing cytotoxicity in transfected cells (Burgos et al., 2021); Has not been previously published as pathogenic or benign in association with neuromuscular disorders to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33468626) - |
Myopathy with tubular aggregates;C1861451:Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 152 of the STIM1 protein (p.Glu152Lys). This variant is present in population databases (rs143916878, gnomAD 0.06%). This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 33468626). ClinVar contains an entry for this variant (Variation ID: 569843). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STIM1 protein function. Experimental studies have shown that this missense change affects STIM1 function (PMID: 33468626). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
DEOGEN2
Benign
T;T;T;.;.;T;T;T;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;.;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
0.014
.;B;.;.;.;.;.;.;.
Vest4
0.55, 0.54, 0.56
MVP
MPC
0.49
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