chr11-4086830-G-A

Variant names:

• chr11-4086830-G-A
• rs562406813
• ENST00000616714.4:c.1828G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001277961.3(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. 10/12 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 NM_001277961.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.851
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P
• Stormorken syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, PanelApp Australia
• tubular aggregate myopathy

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

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

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 461722.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277961.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIM1	NM_001382567.1	MANE Select	c.1634+287G>A		intron	N/A	NP_001369496.1	H0YDB2
	STIM1	NM_001277961.3		c.1828G>A	p.Ala610Thr	missense	Exon 11 of 12	NP_001264890.1	G0XQ39
	STIM1	NM_001382566.1		c.1606G>A	p.Ala536Thr	missense	Exon 11 of 12	NP_001369495.1	A0A8V8TNW0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIM1	ENST00000616714.4	TSL:1	c.1828G>A	p.Ala610Thr	missense	Exon 11 of 12	ENSP00000478059.1	G0XQ39
	STIM1	ENST00000526596.2	TSL:5 MANE Select	c.1634+287G>A		intron	N/A	ENSP00000433266.2	H0YDB2
	STIM1	ENST00000300737.8	TSL:1	c.1541+287G>A		intron	N/A	ENSP00000300737.4	Q13586-1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152148 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00148 AC: 200 AN: 134734 AF XY: 0.00133

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 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.: 8 Cov.: 31 AF XY: 0.00192 AC XY: 1307 AN XY: 682348

African (AFR) AF: 0.000348 AC: 11 AN: 31564

American (AMR) AF: 0.000336 AC: 12 AN: 35670

Ashkenazi Jewish (ASJ) AF: 0.00139 AC: 35 AN: 25148

East Asian (EAS) AF: 0.00 AC: 0 AN: 35710

South Asian (SAS) AF: 0.000922 AC: 73 AN: 79206

European-Finnish (FIN) AF: 0.00163 AC: 56 AN: 34428

Middle Eastern (MID) AF: 0.00228 AC: 13 AN: 5690

European-Non Finnish (NFE) AF: 0.00218 AC: 2355 AN: 1077946

Other (OTH) AF: 0.00150 AC: 87 AN: 57862

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74442

African (AFR) AF: 0.000361 AC: 15 AN: 41554

American (AMR) AF: 0.00118 AC: 18 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00266 AC: 181 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00233 Hom.: 0

Bravo AF: 0.00141

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ExAC AF: 0.000895 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Myopathy with tubular aggregates;C1861451:Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency (1)
-	-	1	STIM1-related disorder (1)
-	1	-	Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency;C4011726:Myopathy, tubular aggregate, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.60
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0082	T
PhyloP100		0.85
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.67	T
Vest4		0.063
MVP		0.56
GERP RS		-1.4
gMVP		0.13
Mutation Taster		=100/0	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: rs562406813; hg19: chr11-4108060;