rs141215990

chr11-4091311-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 5.12

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 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=3, Uncertain_significance=2, Benign=1}. 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 GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIM1	NM_001382567.1	c.1664C>T	p.Ser555Phe	missense_variant	13/13	ENST00000526596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIM1	ENST00000526596.2	c.1664C>T	p.Ser555Phe	missense_variant	13/13	5	NM_001382567.1	P3

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152248 Hom.: 0 Cov.: 32

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.: 2 AF XY: 0.00199 AC XY: 271 AN XY: 135886

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.: 9 Cov.: 31 AF XY: 0.00193 AC XY: 1403 AN XY: 727244

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.: 0 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74510

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.: 0

Bravo AF: 0.00172

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00161 AC: 195

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

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

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, criteria provided, single submitter

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

Invitae

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	26
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	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
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	T
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

Other links and lift over

dbSNP: rs141215990; hg19: chr11-4112541; COSMIC: COSV104613770; COSMIC: COSV104613770;