rs146873551

Variant names:

• chr11-4086513-C-T
• rs146873551
• NM_001382567.1:c.1604C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001382567.1(STIM1):​c.1604C>T​(p.Thr535Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 1,614,180 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T535A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: STIM1 NM_001382567.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.81
• Publications: 6 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004860252).
• BP6: Variant 11-4086513-C-T is Benign according to our data. Variant chr11-4086513-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00252 (384/152340) while in subpopulation AFR AF = 0.00825 (343/41570). AF 95% confidence interval is 0.00753. There are 1 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1604C>T	p.Thr535Met	missense	Exon 12 of 13	NP_001369496.1	H0YDB2
	STIM1	NM_001277961.3		c.1511C>T	p.Thr504Met	missense	Exon 11 of 12	NP_001264890.1	G0XQ39
	STIM1	NM_001382566.1		c.1289C>T	p.Thr430Met	missense	Exon 11 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.1604C>T	p.Thr535Met	missense	Exon 12 of 13	ENSP00000433266.2	H0YDB2
	STIM1	ENST00000616714.4	TSL:1	c.1511C>T	p.Thr504Met	missense	Exon 11 of 12	ENSP00000478059.1	G0XQ39
	STIM1	ENST00000300737.8	TSL:1	c.1511C>T	p.Thr504Met	missense	Exon 11 of 12	ENSP00000300737.4	Q13586-1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 381 AN: 152222 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000629 AC: 158 AN: 251100 AF XY: 0.000449

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000284 AC: 415 AN: 1461840 Hom.: 1 Cov.: 32 AF XY: 0.000267 AC XY: 194 AN XY: 727214

African (AFR) AF: 0.00717 AC: 240 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1111990

Other (OTH) AF: 0.000480 AC: 29 AN: 60392

GnomAD4 genome AF: 0.00252 AC: 384 AN: 152340 Hom.: 1 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74486

African (AFR) AF: 0.00825 AC: 343 AN: 41570

American (AMR) AF: 0.00183 AC: 28 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68034

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00113 Hom.: 5

Bravo AF: 0.00294

ESP6500AA AF: 0.00818 AC: 36

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000840 AC: 102

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Myopathy with tubular aggregates;C1861451:Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.082
Sift	Benign	0.064	T
Sift4G	Benign	0.35	T
Polyphen		0.012	B
Vest4		0.33
MVP		0.33
MPC		0.50
ClinPred		0.012	T
GERP RS		3.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.018
gMVP		0.45
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146873551; hg19: chr11-4107743;