11-4083515-C-G

Variant names:

• chr11-4083515-C-G
• rs2289570
• NM_001382567.1:c.1474+17C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382567.1(STIM1):​c.1474+17C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.899 in 1,605,604 control chromosomes in the GnomAD database, including 653,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (52079 hom., cov: 34)
  • Exomes 𝑓: 0.91 (601810 hom.)
• Consequence: STIM1 NM_001382567.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.162
• Publications: 9 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-4083515-C-G is Benign according to our data. Variant chr11-4083515-C-G is described in ClinVar as Benign. ClinVar VariationId is 258971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STIM1	NM_001382567.1	c.1474+17C>G		intron_variant	Intron 10 of 12	ENST00000526596.2	NP_001369496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STIM1	ENST00000526596.2	c.1474+17C>G		intron_variant	Intron 10 of 12	5	NM_001382567.1	ENSP00000433266.2

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123469 AN: 152094 Hom.: 52060 Cov.: 34

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.868

Gnomad EAS AF: 0.953

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.915

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.912

Gnomad OTH AF: 0.838

GnomAD2 exomes AF: 0.894 AC: 209952 AN: 234868 AF XY: 0.900

Gnomad AFR exome AF: 0.539

Gnomad AMR exome AF: 0.941

Gnomad ASJ exome AF: 0.863

Gnomad EAS exome AF: 0.949

Gnomad FIN exome AF: 0.908

Gnomad NFE exome AF: 0.909

Gnomad OTH exome AF: 0.898

GnomAD4 exome AF: 0.908 AC: 1319467 AN: 1453392 Hom.: 601810 Cov.: 38 AF XY: 0.909 AC XY: 656982 AN XY: 722502

African (AFR) AF: 0.531 AC: 17685 AN: 33298

American (AMR) AF: 0.935 AC: 40279 AN: 43072

Ashkenazi Jewish (ASJ) AF: 0.862 AC: 22402 AN: 25976

East Asian (EAS) AF: 0.960 AC: 37776 AN: 39346

South Asian (SAS) AF: 0.935 AC: 79691 AN: 85276

European-Finnish (FIN) AF: 0.915 AC: 48468 AN: 52992

Middle Eastern (MID) AF: 0.858 AC: 4935 AN: 5752

European-Non Finnish (NFE) AF: 0.916 AC: 1014744 AN: 1107574

Other (OTH) AF: 0.890 AC: 53487 AN: 60106

GnomAD4 genome AF: 0.812 AC: 123528 AN: 152212 Hom.: 52079 Cov.: 34 AF XY: 0.815 AC XY: 60691 AN XY: 74436

African (AFR) AF: 0.551 AC: 22841 AN: 41468

American (AMR) AF: 0.890 AC: 13617 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.868 AC: 3014 AN: 3472

East Asian (EAS) AF: 0.953 AC: 4943 AN: 5186

South Asian (SAS) AF: 0.935 AC: 4516 AN: 4828

European-Finnish (FIN) AF: 0.915 AC: 9719 AN: 10620

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.912 AC: 62046 AN: 68020

Other (OTH) AF: 0.837 AC: 1764 AN: 2108

Alfa AF: 0.854 Hom.: 6767

Bravo AF: 0.795

Asia WGS AF: 0.921 AC: 3204 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 98% of patients studied by a panel of primary immunodeficiencies. Number of patients: 93. Only high quality variants are reported. -

Oct 19, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Combined immunodeficiency due to STIM1 deficiency Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stormorken syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, tubular aggregate, 1 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy with tubular aggregates;C1861451:Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.4
DANN	Benign	0.61
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2289570; hg19: chr11-4104745;