rs3750994

Variant names:

• chr11-4092240-T-G
• rs3750994
• NM_001382567.1:c.*442T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001382567.1(STIM1):​c.*442T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 300,074 control chromosomes in the GnomAD database, including 504 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.038 (263 hom., cov: 32)
  • Exomes 𝑓: 0.035 (241 hom.)
• Consequence: STIM1 NM_001382567.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.383
• Publications: 12 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STIM1	NM_001382567.1	c.*442T>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000526596.2	NP_001369496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STIM1	ENST00000526596.2	c.*442T>G		3_prime_UTR_variant	Exon 13 of 13	5	NM_001382567.1	ENSP00000433266.2

Frequencies

GnomAD3 genomes AF: 0.0378 AC: 5747 AN: 152184 Hom.: 259 Cov.: 32

Gnomad AFR AF: 0.00974

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0970

Gnomad ASJ AF: 0.0384

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0655

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0368

GnomAD4 exome AF: 0.0347 AC: 5124 AN: 147772 Hom.: 241 Cov.: 0 AF XY: 0.0333 AC XY: 2627 AN XY: 78850

African (AFR) AF: 0.0109 AC: 53 AN: 4874

American (AMR) AF: 0.123 AC: 906 AN: 7338

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 116 AN: 3572

East Asian (EAS) AF: 0.185 AC: 1298 AN: 7018

South Asian (SAS) AF: 0.0160 AC: 416 AN: 25974

European-Finnish (FIN) AF: 0.0379 AC: 204 AN: 5386

Middle Eastern (MID) AF: 0.0169 AC: 9 AN: 534

European-Non Finnish (NFE) AF: 0.0215 AC: 1841 AN: 85536

Other (OTH) AF: 0.0373 AC: 281 AN: 7540

GnomAD4 genome AF: 0.0379 AC: 5769 AN: 152302 Hom.: 263 Cov.: 32 AF XY: 0.0417 AC XY: 3103 AN XY: 74470

African (AFR) AF: 0.00974 AC: 405 AN: 41582

American (AMR) AF: 0.0977 AC: 1494 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0384 AC: 133 AN: 3468

East Asian (EAS) AF: 0.194 AC: 1003 AN: 5172

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4826

European-Finnish (FIN) AF: 0.0655 AC: 695 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0253 AC: 1722 AN: 68024

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

Alfa AF: 0.0340 Hom.: 308

Bravo AF: 0.0422

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.64
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3750994; hg19: chr11-4113470;