rs3750996

Variant names:

• chr11-4091970-A-G
• rs3750996
• NM_001382567.1:c.*172A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382567.1(STIM1):​c.*172A>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 0.0152 in 898,664 control chromosomes in the GnomAD database, including 1,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (125 hom., cov: 32)
  • Exomes 𝑓: 0.016 (896 hom.)
• Consequence: STIM1 NM_001382567.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.63
• Publications: 19 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P
• Stormorken syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, PanelApp Australia
• tubular aggregate myopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• combined immunodeficiency due to STIM1 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-4091970-A-G is Benign according to our data. Variant chr11-4091970-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1219172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382567.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIM1	NM_001382567.1	MANE Select	c.*172A>G		3_prime_UTR	Exon 13 of 13	NP_001369496.1	H0YDB2
	STIM1	NM_001277961.3		c.*172A>G		3_prime_UTR	Exon 12 of 12	NP_001264890.1	G0XQ39
	STIM1	NM_001382566.1		c.*172A>G		3_prime_UTR	Exon 12 of 12	NP_001369495.1	A0A8V8TNW0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIM1	ENST00000526596.2	TSL:5 MANE Select	c.*172A>G		3_prime_UTR	Exon 13 of 13	ENSP00000433266.2	H0YDB2
	STIM1	ENST00000616714.4	TSL:1	c.*172A>G		3_prime_UTR	Exon 12 of 12	ENSP00000478059.1	G0XQ39
	STIM1	ENST00000300737.8	TSL:1	c.*172A>G		3_prime_UTR	Exon 12 of 12	ENSP00000300737.4	Q13586-1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1632 AN: 151900 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.0161 AC: 12014 AN: 746646 Hom.: 896 Cov.: 10 AF XY: 0.0183 AC XY: 7022 AN XY: 384526

African (AFR) AF: 0.000694 AC: 13 AN: 18724

American (AMR) AF: 0.0100 AC: 293 AN: 29204

Ashkenazi Jewish (ASJ) AF: 0.000274 AC: 5 AN: 18222

East Asian (EAS) AF: 0.202 AC: 6585 AN: 32522

South Asian (SAS) AF: 0.0713 AC: 4197 AN: 58856

European-Finnish (FIN) AF: 0.000476 AC: 15 AN: 31540

Middle Eastern (MID) AF: 0.00295 AC: 8 AN: 2712

European-Non Finnish (NFE) AF: 0.000455 AC: 236 AN: 518580

Other (OTH) AF: 0.0182 AC: 662 AN: 36286

GnomAD4 genome AF: 0.0107 AC: 1627 AN: 152018 Hom.: 125 Cov.: 32 AF XY: 0.0127 AC XY: 944 AN XY: 74286

African (AFR) AF: 0.00130 AC: 54 AN: 41474

American (AMR) AF: 0.00510 AC: 78 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.210 AC: 1081 AN: 5146

South Asian (SAS) AF: 0.0737 AC: 354 AN: 4806

European-Finnish (FIN) AF: 0.000473 AC: 5 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000427 AC: 29 AN: 67966

Other (OTH) AF: 0.0119 AC: 25 AN: 2100

Alfa AF: 0.00235 Hom.: 11

Bravo AF: 0.0106

Asia WGS AF: 0.106 AC: 368 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		1.6
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: rs3750996; hg19: chr11-4113200; COSMIC: COSV56157285; COSMIC: COSV56157285;