Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_001382567.1(STIM1):c.221T>C(p.Leu74Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

STIM1
NM_001382567.1 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.57

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001382567.1

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-3967633-T-C is Pathogenic according to our data. Variant chr11-3967633-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 375471.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382567.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STIM1	NM_001382567.1	MANE Select	c.221T>C	p.Leu74Pro	missense	Exon 2 of 13	NP_001369496.1
STIM1	NM_001277961.3		c.221T>C	p.Leu74Pro	missense	Exon 2 of 12	NP_001264890.1
STIM1	NM_001382568.1		c.221T>C	p.Leu74Pro	missense	Exon 2 of 12	NP_001369497.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STIM1	ENST00000526596.2	TSL:5 MANE Select	c.221T>C	p.Leu74Pro	missense	Exon 2 of 13	ENSP00000433266.2
STIM1	ENST00000616714.4	TSL:1	c.221T>C	p.Leu74Pro	missense	Exon 2 of 12	ENSP00000478059.1
STIM1	ENST00000300737.8	TSL:1	c.221T>C	p.Leu74Pro	missense	Exon 2 of 12	ENSP00000300737.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined immunodeficiency due to STIM1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.72

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.55

PhyloP100

3.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.44

REVEL

Uncertain

0.29

Sift

Benign

0.045

Sift4G

Uncertain

0.046

Polyphen

0.42

Vest4

0.83

MutPred

0.38

Loss of stability (P = 0.0038)

MVP

0.84

MPC

0.89

ClinPred

0.54

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.91

Mutation Taster

=10/90

disease causing (ClinVar)

(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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rs1057519506

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

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