chr11-4082873-T-C

Position:

• chr11-4082873-T-C

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.1138-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,658 control chromosomes in the GnomAD database, including 1,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (505 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (526 hom.)
• Consequence: STIM1 NM_001382567.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001623
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.948

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 (BayesDel_noAF=-0.48).
• BP6: Variant 11-4082873-T-C is Benign according to our data. Variant chr11-4082873-T-C is described in ClinVar as [Benign]. Clinvar id is 258967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIM1	NM_001382567.1	c.1138-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000526596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIM1	ENST00000526596.2	c.1138-9T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001382567.1	P3

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 6992 AN: 152162 Hom.: 502 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0141 AC: 3534 AN: 251290 Hom.: 189 AF XY: 0.0109 AC XY: 1487 AN XY: 135800

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00395

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00357

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00749 AC: 10950 AN: 1461378 Hom.: 526 Cov.: 33 AF XY: 0.00688 AC XY: 5002 AN XY: 727012

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.00605

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00435

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00314

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0460 AC: 7010 AN: 152280 Hom.: 505 Cov.: 32 AF XY: 0.0440 AC XY: 3278 AN XY: 74482

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00356

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0232 Hom.: 103

Bravo AF: 0.0524

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00468

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

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
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.050
SpliceAI score (max)		0.090		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: rs58461583; hg19: chr11-4104103;