rs61743670

chr11-4091543-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001382567.1(STIM1):c.1896C>G(p.Pro632=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,614,204 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (117 hom.)
• Consequence: STIM1 NM_001382567.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.535

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 11-4091543-C-G is Benign according to our data. Variant chr11-4091543-C-G is described in ClinVar as [Benign]. Clinvar id is 258974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-4091543-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.535 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00358 (546/152310) while in subpopulation SAS AF= 0.0381 (184/4830). AF 95% confidence interval is 0.0336. There are 2 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIM1	NM_001382567.1	c.1896C>G	p.Pro632=	synonymous_variant	13/13	ENST00000526596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIM1	ENST00000526596.2	c.1896C>G	p.Pro632=	synonymous_variant	13/13	5	NM_001382567.1	P3

Frequencies

GnomAD3 genomes AF: 0.00360 AC: 548 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0218

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00953 AC: 2396 AN: 251370 Hom.: 45 AF XY: 0.0107 AC XY: 1453 AN XY: 135874

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.0176

Gnomad SAS exome AF: 0.0454

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00413 AC: 6038 AN: 1461894 Hom.: 117 Cov.: 31 AF XY: 0.00517 AC XY: 3760 AN XY: 727248

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0159

Gnomad4 ASJ exome AF: 0.00348

Gnomad4 EAS exome AF: 0.0131

Gnomad4 SAS exome AF: 0.0430

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000528

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.00358 AC: 546 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00420 AC XY: 313 AN XY: 74482

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0217

Gnomad4 SAS AF: 0.0381

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.00325

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000948

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2017	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. -

Myopathy with tubular aggregates;C1861451:Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	7.0
Dann	Benign	0.79

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: rs61743670; hg19: chr11-4112773;