rs562406813

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The ENST00000616714.4(STIM1):c.1828G>A(p.Ala610Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,535,490 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 8 hom. )

Consequence

STIM1
ENST00000616714.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.851

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008152604).

BP6

Variant 11-4086830-G-A is Benign according to our data. Variant chr11-4086830-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461722.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00153 (233/152266) while in subpopulation NFE AF= 0.00266 (181/68026). AF 95% confidence interval is 0.00234. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIM1	NM_001382567.1 linkuse as main transcript	c.1634+287G>A		intron_variant		ENST00000526596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIM1	ENST00000526596.2 linkuse as main transcript	c.1634+287G>A		intron_variant		5	NM_001382567.1	P3

Frequencies

GnomAD3 genomes

AF:

0.00152

AC:

232

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00266

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00148

AC:

200

AN:

134734

Hom.:

AF XY:

0.00133

AC XY:

AN XY:

73082

show subpopulations

Gnomad AFR exome

AF:

0.000153

Gnomad AMR exome

AF:

0.000327

Gnomad ASJ exome

AF:

0.00145

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000756

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.00280

Gnomad OTH exome

AF:

0.00121

GnomAD4 exome

AF:

0.00191

AC:

2642

AN:

1383224

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

1307

AN XY:

682348

show subpopulations

Gnomad4 AFR exome

AF:

0.000348

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.00139

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000922

Gnomad4 FIN exome

AF:

0.00163

Gnomad4 NFE exome

AF:

0.00218

Gnomad4 OTH exome

AF:

0.00150

GnomAD4 genome

AF:

0.00153

AC:

233

AN:

152266

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00266

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00233

Hom.:

Bravo

AF:

0.00141

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ExAC

AF:

0.000895

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2021	In silico analysis supports that this variant does not alter splicing; Identified in two related patients with inherited thrombocytopenia, although these patients had a variant in the GFI1B gene that may have also contributed to the phenotype (Johnson et al., 2016); This variant is associated with the following publications: (PMID: 27479822) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	STIM1: BP4, BS2 -

Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency;C4011726:Myopathy, tubular aggregate, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

STIM1 NM_001277961.1 exon 11 p.Ala610Thr (c.1828G>A): This variant has been reported in the literature in 1 individual with cutaneous bruising with clinical suspicion for thrombocytopenia of unknown etiology, segregating with disease in 1 affected family member. However, both of these individuals also carried an additional variant of potential clinical significance in a different gene (GFI1B c.814+1G>A) (Johnson 2016 PMID:27479822). This variant is present in 0.2% (202/68194) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-4108060-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:461722). This variant amino acid Threonine (Thr) is present in several species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

STIM1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

Cadd

Benign

Dann

Benign

0.60

DEOGEN2

Benign

0.20

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0082

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.30

Sift4G

Benign

0.67

Vest4

0.063

MVP

0.56

GERP RS

-1.4

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over