Genetic Variant STIM1:p.Val129Val (chr11-4055527-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001382567.1(STIM1):c.387A>G(p.Val129Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000866 in 1,592,364 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 18 hom. )

Consequence

STIM1
NM_001382567.1 splice_region, synonymous

Scores

Splicing: ADA: 0.0001453

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.384

Publications

5 publications found

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 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)

STIM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 11-4055527-A-G is Benign according to our data. Variant chr11-4055527-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.384 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00118 (180/152344) while in subpopulation EAS AF = 0.0283 (147/5186). AF 95% confidence interval is 0.0246. There are 5 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STIM1	NM_001382567.1	MANE Select	c.387A>G	p.Val129Val	splice_region synonymous	Exon 4 of 13	NP_001369496.1
STIM1	NM_001382581.1		c.-103A>G		splice_region	Exon 3 of 11	NP_001369510.1
STIM1	NM_001382580.1		c.-103A>G		splice_region	Exon 3 of 12	NP_001369509.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STIM1	ENST00000526596.2	TSL:5 MANE Select	c.387A>G	p.Val129Val	splice_region synonymous	Exon 4 of 13	ENSP00000433266.2
STIM1	ENST00000616714.4	TSL:1	c.387A>G	p.Val129Val	splice_region synonymous	Exon 4 of 12	ENSP00000478059.1
STIM1	ENST00000300737.8	TSL:1	c.387A>G	p.Val129Val	splice_region synonymous	Exon 4 of 12	ENSP00000300737.4

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

180

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0283

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00272

AC:

599

AN:

219978

AF XY:

0.00267

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000959

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0325

Gnomad FIN exome

AF:

0.0000530

Gnomad NFE exome

AF:

0.0000612

Gnomad OTH exome

AF:

0.000909

GnomAD4 exome

AF:

0.000833

AC:

1199

AN:

1440020

Hom.:

Cov.:

AF XY:

0.000909

AC XY:

649

AN XY:

714090

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33206

American (AMR)

AF:

0.0000956

AC:

AN:

41848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25716

East Asian (EAS)

AF:

0.0223

AC:

874

AN:

39192

South Asian (SAS)

AF:

0.00224

AC:

185

AN:

82440

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52264

Middle Eastern (MID)

AF:

0.000237

AC:

AN:

4212

European-Non Finnish (NFE)

AF:

0.0000490

AC:

AN:

1101590

Other (OTH)

AF:

0.00134

AC:

AN:

59552

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00118

AC:

180

AN:

152344

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.000327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0283

AC:

147

AN:

5186

South Asian (SAS)

AF:

0.00352

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68036

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.00205

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Oct 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

6.1

(source)

DANN

Benign

0.53

PhyloP100

0.38

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.010

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over