rs141215990

Positions:

chr11-4091311-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001382567.1(STIM1):c.1664C>T(p.Ser555Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00182 in 1,614,246 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 9 hom. )

Consequence

STIM1
NM_001382567.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 5.12

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0089687705).

BP6

Variant 11-4091311-C-T is Benign according to our data. Variant chr11-4091311-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235347.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}. Variant chr11-4091311-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00161 (246/152366) while in subpopulation AMR AF= 0.00281 (43/15306). AF 95% confidence interval is 0.00214. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STIM1	NM_001382567.1 linkuse as main transcript	c.1664C>T	p.Ser555Phe	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.1664C>T	p.Ser555Phe	missense_variant	13/13	5	NM_001382567.1	ENSP00000433266	P3

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

247

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00181

AC:

456

AN:

251390

Hom.:

AF XY:

0.00199

AC XY:

271

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00446

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00323

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00201

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00184

AC:

2687

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

1403

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.00490

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00333

Gnomad4 FIN exome

AF:

0.000506

Gnomad4 NFE exome

AF:

0.00183

Gnomad4 OTH exome

AF:

0.00215

GnomAD4 genome

AF:

0.00161

AC:

246

AN:

152366

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00222

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00222

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00161

AC:

195

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00262

EpiControl

AF:

0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	STIM1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Aug 13, 2020

STIM1 NM_003156.3 exon 12 p.Ser524Phe (c.1571C>T): This variant has not been reported in the literature but is present in 0.3% (99/30616) of South Asian alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-4112541-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:235347). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

STIM1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.0090

T;T;T

MetaSVM

Benign

-0.63

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.5

N;.;D

REVEL

Benign

0.21

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.99

D;.;.

Vest4

0.55

MVP

0.58

MPC

1.3

ClinPred

0.057

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.60

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