rs527236030

Variant names:

• chr11-4023945-A-T
• rs527236030
• NM_001382567.1:c.343A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001382567.1(STIM1):​c.343A>T​(p.Ile115Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STIM1 NM_001382567.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 8.71

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• PP5: Variant 11-4023945-A-T is Pathogenic according to our data. Variant chr11-4023945-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 143191.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STIM1	NM_001382567.1	c.343A>T	p.Ile115Phe	missense_variant	Exon 3 of 13	ENST00000526596.2	NP_001369496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STIM1	ENST00000526596.2	c.343A>T	p.Ile115Phe	missense_variant	Exon 3 of 13	5	NM_001382567.1	ENSP00000433266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

-

Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Myopathy, tubular aggregate, 1 Pathogenic:1

Mar 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Stormorken syndrome Pathogenic:1

Mar 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Apr 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to be de novo in individuals affected with tubular aggregate myopathy and York platelet syndrome (YPS) and segregates in a family affected with YPS (PMID: 24570283, 25577287). ClinVar contains an entry for this variant (Variation ID: 143191). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with phenylalanine at codon 115 of the STIM1 protein (p.Ile115Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;D;D;.;.;D;D;D;D;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.1	.;M;.;M;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.9	D;D;.;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.0040	.;B;.;.;.;.;.;.;.;.;.
Vest4		0.99, 0.99, 0.97
MutPred		0.69		.;Loss of ubiquitination at K113 (P = 0.0982);Loss of ubiquitination at K113 (P = 0.0982);Loss of ubiquitination at K113 (P = 0.0982);.;.;.;.;.;.;.;
MVP		0.95
MPC		0.69
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.77
gMVP		0.94

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

Other links and lift over

dbSNP: rs527236030; hg19: chr11-4045175;