chr11-4091578-C-A

Variant names:

• chr11-4091578-C-A
• rs35637264
• NM_001382567.1:c.1931C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001382567.1(STIM1):​c.1931C>A​(p.Ser644Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000551 in 1,614,204 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts 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. S644F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: STIM1 NM_001382567.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.93
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063069165).
• BP6: Variant 11-4091578-C-A is Benign according to our data. Variant chr11-4091578-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461726.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 = 0.00298 (454/152310) while in subpopulation AFR AF = 0.0103 (429/41566). AF 95% confidence interval is 0.00951. There are 2 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.1931C>A	p.Ser644Tyr	missense	Exon 13 of 13	NP_001369496.1	H0YDB2
	STIM1	NM_001277961.3		c.2156C>A	p.Ser719Tyr	missense	Exon 12 of 12	NP_001264890.1	G0XQ39
	STIM1	NM_001382566.1		c.1934C>A	p.Ser645Tyr	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.1931C>A	p.Ser644Tyr	missense	Exon 13 of 13	ENSP00000433266.2	H0YDB2
	STIM1	ENST00000616714.4	TSL:1	c.2156C>A	p.Ser719Tyr	missense	Exon 12 of 12	ENSP00000478059.1	G0XQ39
	STIM1	ENST00000300737.8	TSL:1	c.1838C>A	p.Ser613Tyr	missense	Exon 12 of 12	ENSP00000300737.4	Q13586-1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152194 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000692 AC: 174 AN: 251448 AF XY: 0.000530

Gnomad AFR exome AF: 0.00990

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000298 AC: 435 AN: 1461894 Hom.: 1 Cov.: 31 AF XY: 0.000249 AC XY: 181 AN XY: 727248

African (AFR) AF: 0.0109 AC: 364 AN: 33480

American (AMR) AF: 0.000335 AC: 15 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: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112012

Other (OTH) AF: 0.000778 AC: 47 AN: 60396

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74486

African (AFR) AF: 0.0103 AC: 429 AN: 41566

American (AMR) AF: 0.00111 AC: 17 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000928 Hom.: 4

Bravo AF: 0.00340

ESP6500AA AF: 0.00886 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Myopathy with tubular aggregates;C1861451:Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0063	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.33
MVP		0.65
MPC		1.4
ClinPred		0.056	T
GERP RS		4.7
Varity_R		0.46
gMVP		0.61
Mutation Taster		=46/54	disease causing

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: rs35637264; hg19: chr11-4112808;