chr11-4091694-G-A

Variant names:

• chr11-4091694-G-A
• rs201992816
• NM_001382567.1:c.2047G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382567.1(STIM1):​c.2047G>A​(p.Ala683Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A683S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STIM1 NM_001382567.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Stormorken syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• tubular aggregate myopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• combined immunodeficiency due to STIM1 deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10190517).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIM1	NM_001382567.1	MANE Select	c.2047G>A	p.Ala683Thr	missense	Exon 13 of 13	NP_001369496.1
	STIM1	NM_001277961.3		c.2272G>A	p.Ala758Thr	missense	Exon 12 of 12	NP_001264890.1
	STIM1	NM_001382566.1		c.2050G>A	p.Ala684Thr	missense	Exon 12 of 12	NP_001369495.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIM1	ENST00000526596.2	TSL:5 MANE Select	c.2047G>A	p.Ala683Thr	missense	Exon 13 of 13	ENSP00000433266.2
	STIM1	ENST00000616714.4	TSL:1	c.2272G>A	p.Ala758Thr	missense	Exon 12 of 12	ENSP00000478059.1
	STIM1	ENST00000300737.8	TSL:1	c.1954G>A	p.Ala652Thr	missense	Exon 12 of 12	ENSP00000300737.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.081
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.064
Sift	Uncertain	0.026	D
Sift4G	Benign	0.24	T
Polyphen		0.099	B
Vest4		0.12
MutPred		0.22		Gain of phosphorylation at A652 (P = 0.0058)
MVP		0.43
MPC		0.41
ClinPred		0.70	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.12
gMVP		0.17
Mutation Taster		=73/27	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: rs201992816; hg19: chr11-4112924;