rs397515436

Positions:

• chr11-3967628-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001382567.1(STIM1):​c.216C>A​(p.His72Gln) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STIM1 NM_001382567.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.23

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 11-3967628-C-A is Pathogenic according to our data. Variant chr11-3967628-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3233243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-3967628-C-A is described in Lovd as [Pathogenic]. Variant chr11-3967628-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STIM1	NM_001382567.1	c.216C>A	p.His72Gln	missense_variant	2/13	ENST00000526596.2	NP_001369496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STIM1	ENST00000526596.2	c.216C>A	p.His72Gln	missense_variant	2/13	5	NM_001382567.1	ENSP00000433266	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, autophagic vacuolar, infantile-onset Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PM1+PM2+PP1+PP3+PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.1	D;.;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.99
MutPred		0.62		Gain of ubiquitination at K73 (P = 0.0898);Gain of ubiquitination at K73 (P = 0.0898);Gain of ubiquitination at K73 (P = 0.0898);
MVP		0.98
MPC		1.3
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.87
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515436; hg19: chr11-3988858;