rs3750996

Positions:

• chr11-4091970-A-G

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.*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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STIM1	NM_001382567.1	c.*172A>G		3_prime_UTR_variant	13/13	ENST00000526596.2	NP_001369496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STIM1	ENST00000526596.2	c.*172A>G		3_prime_UTR_variant	13/13	5	NM_001382567.1	ENSP00000433266.2

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

Gnomad4 AFR exome AF: 0.000694

Gnomad4 AMR exome AF: 0.0100

Gnomad4 ASJ exome AF: 0.000274

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.0713

Gnomad4 FIN exome AF: 0.000476

Gnomad4 NFE exome AF: 0.000455

Gnomad4 OTH exome AF: 0.0182

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

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.210

Gnomad4 SAS AF: 0.0737

Gnomad4 FIN AF: 0.000473

Gnomad4 NFE AF: 0.000427

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00227 Hom.: 8

Bravo AF: 0.0106

Asia WGS AF: 0.106 AC: 368 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.90

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: rs3750996; hg19: chr11-4113200; COSMIC: COSV56157285; COSMIC: COSV56157285;