11-4090670-A-G

Variant names:

• chr11-4090670-A-G
• rs3794050
• NM_001382567.1:c.1635-612A>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.1635-612A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 152,106 control chromosomes in the GnomAD database, including 45,857 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 0.76 (45857 hom., cov: 31)
• Consequence: STIM1 NM_001382567.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.527
• Publications: 9 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=-0.69).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STIM1	NM_001382567.1	c.1635-612A>G		intron_variant	Intron 12 of 12	ENST00000526596.2	NP_001369496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STIM1	ENST00000526596.2	c.1635-612A>G		intron_variant	Intron 12 of 12	5	NM_001382567.1	ENSP00000433266.2

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115212 AN: 151988 Hom.: 45863 Cov.: 31

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.782

Gnomad AMR AF: 0.785

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.850

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.882

Gnomad OTH AF: 0.783

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.758 AC: 115239 AN: 152106 Hom.: 45857 Cov.: 31 AF XY: 0.759 AC XY: 56418 AN XY: 74358

African (AFR) AF: 0.490 AC: 20284 AN: 41436

American (AMR) AF: 0.785 AC: 12009 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2965 AN: 3468

East Asian (EAS) AF: 0.764 AC: 3943 AN: 5162

South Asian (SAS) AF: 0.925 AC: 4466 AN: 4828

European-Finnish (FIN) AF: 0.850 AC: 9003 AN: 10592

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.882 AC: 59982 AN: 68002

Other (OTH) AF: 0.778 AC: 1645 AN: 2114

Alfa AF: 0.855 Hom.: 28701

Bravo AF: 0.736

Asia WGS AF: 0.778 AC: 2706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.66
PhyloP100		0.53
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: rs3794050; hg19: chr11-4111900;