rs35960304

chr11-4091352-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382567.1(STIM1):c.1705C>T(p.Pro569Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,614,238 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (74 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (84 hom.)
• Consequence: STIM1 NM_001382567.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.680

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001496464).
• BP6: Variant 11-4091352-C-T is Benign according to our data. Variant chr11-4091352-C-T is described in ClinVar as [Benign]. Clinvar id is 258973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-4091352-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIM1	NM_001382567.1	c.1705C>T	p.Pro569Ser	missense_variant	13/13	ENST00000526596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIM1	ENST00000526596.2	c.1705C>T	p.Pro569Ser	missense_variant	13/13	5	NM_001382567.1	P3

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2694 AN: 152232 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00450 AC: 1132 AN: 251432 Hom.: 30 AF XY: 0.00314 AC XY: 427 AN XY: 135900

Gnomad AFR exome AF: 0.0615

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00182 AC: 2654 AN: 1461888 Hom.: 84 Cov.: 31 AF XY: 0.00156 AC XY: 1135 AN XY: 727244

Gnomad4 AFR exome AF: 0.0657

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.0177 AC: 2704 AN: 152350 Hom.: 74 Cov.: 32 AF XY: 0.0170 AC XY: 1264 AN XY: 74510

Gnomad4 AFR AF: 0.0622

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00332 Hom.: 25

Bravo AF: 0.0200

ESP6500AA AF: 0.0668 AC: 294

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00564 AC: 685

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2016	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. -

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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	19
Dann	Benign	0.93
DEOGEN2	Benign	0.23	T;T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	0.69	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.31	N;.;N
REVEL	Benign	0.11
Sift	Benign	0.25	T;.;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.023
MVP		0.32
MPC		0.43
ClinPred		0.0076	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.14

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: rs35960304; hg19: chr11-4112582;