rs750326949

Positions:

chr11-4091494-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001382567.1(STIM1):c.1847C>T(p.Ala616Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

STIM1
NM_001382567.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.15

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 links:

STIM1 (HGNC:):

STIM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.078713685).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000363 (53/1461870) while in subpopulation AMR AF= 0.000358 (16/44724). AF 95% confidence interval is 0.000224. There are 0 homozygotes in gnomad4_exome. There are 27 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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	Protein	UniProt
STIM1	NM_001382567.1 linkuse as main transcript	c.1847C>T	p.Ala616Val	missense_variant	13/13	ENST00000526596.2	NP_001369496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STIM1	ENST00000526596.2 linkuse as main transcript	c.1847C>T	p.Ala616Val	missense_variant	13/13	5	NM_001382567.1	ENSP00000433266.2		H0YDB2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251302

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000200

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 17, 2023

Variant summary: STIM1 c.1754C>T (p.Ala585Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251302 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in STIM1 causing STIM1-Related Disorders (8e-05 vs ND), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1754C>T in individuals affected with STIM1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

STIM1 NM_003156.3 exon 12 p.Ala585Val (c.1754C>T): This variant has not been reported in the literature but is present in 0.03% (13/35436) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-4112724-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:568147). Evolutionary conservation for this variant are unclear; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2024

The c.1754C>T (p.A585V) alteration is located in exon 12 (coding exon 12) of the STIM1 gene. This alteration results from a C to T substitution at nucleotide position 1754, causing the alanine (A) at amino acid position 585 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Myopathy with tubular aggregates;C1861451:Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 585 of the STIM1 protein (p.Ala585Val). This variant is present in population databases (rs750326949, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with STIM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 568147). 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) performed at Invitae indicates that this missense variant is not expected to disrupt STIM1 protein function with a negative predictive value of 80%. 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

0.077

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.23

T;T;T

Eigen

Benign

-0.010

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.85

D;T;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.079

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.020

N;.;N

REVEL

Benign

0.20

Sift

Benign

0.56

T;.;T

Sift4G

Benign

0.65

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.056

MutPred

0.21

Loss of loop (P = 0.0112);.;.;

MVP

0.56

MPC

0.42

ClinPred

0.031

GERP RS

3.2

Varity_R

0.062

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over