chr11-4091700-G-A

Variant names:

• chr11-4091700-G-A
• rs201466902
• NM_001382567.1:c.2053G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001382567.1(STIM1):​c.2053G>A​(p.Ala685Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,614,198 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A685V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: STIM1 NM_001382567.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.85
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05567667).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000144 (22/152362) while in subpopulation SAS AF = 0.00124 (6/4826). AF 95% confidence interval is 0.000541. There are 1 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2053G>A	p.Ala685Thr	missense	Exon 13 of 13	NP_001369496.1	H0YDB2
	STIM1	NM_001277961.3		c.2278G>A	p.Ala760Thr	missense	Exon 12 of 12	NP_001264890.1	G0XQ39
	STIM1	NM_001382566.1		c.2056G>A	p.Ala686Thr	missense	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.2053G>A	p.Ala685Thr	missense	Exon 13 of 13	ENSP00000433266.2	H0YDB2
	STIM1	ENST00000616714.4	TSL:1	c.2278G>A	p.Ala760Thr	missense	Exon 12 of 12	ENSP00000478059.1	G0XQ39
	STIM1	ENST00000300737.8	TSL:1	c.1960G>A	p.Ala654Thr	missense	Exon 12 of 12	ENSP00000300737.4	Q13586-1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251422 AF XY: 0.000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000133 AC: 194 AN: 1461836 Hom.: 1 Cov.: 31 AF XY: 0.000146 AC XY: 106 AN XY: 727216

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86258

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53364

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

European-Non Finnish (NFE) AF: 0.000122 AC: 136 AN: 1112012

Other (OTH) AF: 0.0000828 AC: 5 AN: 60394

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74500

African (AFR) AF: 0.0000481 AC: 2 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	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	0.072
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.026
Sift	Benign	0.057	T
Sift4G	Benign	0.39	T
Polyphen		0.089	B
Vest4		0.11
MVP		0.55
MPC		0.45
ClinPred		0.046	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.16
Mutation Taster		=93/7	polymorphism

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: rs201466902; hg19: chr11-4112930;