11-3856292-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001382567.1(STIM1):c.22G>A(p.Ala8Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: STIM1 NM_001382567.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.91

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35725373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIM1	NM_001382567.1	c.22G>A	p.Ala8Thr	missense_variant	1/13	ENST00000526596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIM1	ENST00000526596.2	c.22G>A	p.Ala8Thr	missense_variant	1/13	5	NM_001382567.1	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251406 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461836 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.22G>A (p.Ala8Thr) in STIM1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain Significance. The p.Ala8Thr variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0007955% is reported in gnomAD. The amino acid Ala at position 8 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Ala8Thr in STIM1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as uncertain significance . -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 14, 2022

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1035654). This variant has not been reported in the literature in individuals affected with STIM1-related conditions. This variant is present in population databases (rs751520286, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 8 of the STIM1 protein (p.Ala8Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.0	N;.;N
MutationTaster	Benign	0.56	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.090	N;.;N
REVEL	Benign	0.24
Sift	Benign	0.26	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.98	D;.;.
Vest4		0.40
MutPred		0.28		Loss of MoRF binding (P = 0.0982);Loss of MoRF binding (P = 0.0982);Loss of MoRF binding (P = 0.0982);
MVP		0.76
MPC		0.78
ClinPred		0.40	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.094
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs751520286; hg19: chr11-3877522;