rs143916878

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.79

Publications

1 publications found

Variant links:

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]

STIM1 Gene-Disease associations (from GenCC):

myopathy, tubular aggregate, 1
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
Stormorken syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
tubular aggregate myopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
combined immunodeficiency due to STIM1 deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

STIM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STIM1	NM_001382567.1 link	c.454G>A	p.Glu152Lys	missense_variant	Exon 4 of 13	ENST00000526596.2	NP_001369496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STIM1	ENST00000526596.2 link	c.454G>A	p.Glu152Lys	missense_variant	Exon 4 of 13	5	NM_001382567.1	ENSP00000433266.2		H0YDB2

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

226676

AF XY:

0.0000985

show subpopulations

Gnomad AFR exome

AF:

0.000214

Gnomad AMR exome

AF:

0.000124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000580

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000537

GnomAD4 exome

AF:

0.0000491

AC:

AN:

1446602

Hom.:

Cov.:

AF XY:

0.0000474

AC XY:

AN XY:

717816

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33294

American (AMR)

AF:

0.0000933

AC:

AN:

42886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25842

East Asian (EAS)

AF:

0.000406

AC:

AN:

39406

South Asian (SAS)

AF:

0.000301

AC:

AN:

83146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4168

European-Non Finnish (NFE)

AF:

0.00000362

AC:

AN:

1105778

Other (OTH)

AF:

0.000351

AC:

AN:

59746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000190

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5184

South Asian (SAS)

AF:

0.00124

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 28, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: STIM1 c.454G>A (p.Glu152Lys) results in a conservative amino acid change located in the Sterile alpha motif/pointed domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 226676 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in STIM1 causing STIM1-Related Disorders, allowing no conclusion about variant significance. c.454G>A has been reported in the literature in heterozygous state in individuals affected with pancreatitis (example: Burgos_2021). These report(s) do not provide unequivocal conclusions about association of the variant with STIM1-Related Disorders. At least one publication reports experimental evidence that this variant changes the normal function of the protein (example: Burgos_2021). The following publication has been ascertained in the context of this evaluation (PMID: 33468626). ClinVar contains an entry for this variant (Variation ID: 569843). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency;C4011726:Myopathy, tubular aggregate, 1

Uncertain:1

Jan 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Oct 04, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 33468626). ClinVar contains an entry for this variant (Variation ID: 569843). Invitae Evidence 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 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.25

T;T;T;.;.;T;T;T;.

Eigen

Benign

0.012

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.038

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.1

.;L;.;L;.;.;.;.;.

PhyloP100

9.8

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.98

N;N;.;N;N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

1.0

T;T;.;T;T;T;T;T;T

Sift4G

Benign

0.72

T;T;T;T;T;T;T;T;T

Polyphen

0.014

.;B;.;.;.;.;.;.;.

Vest4

0.55, 0.54, 0.56

MVP

0.78

MPC

0.49

ClinPred

0.12

GERP RS

5.8

Varity_R

0.17

gMVP

0.44

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over