rs587777610

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_198282.4(STING1):c.463G>A(p.Val155Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

STING1
NM_198282.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.64

Publications

128 publications found

Variant links:

Genes affected

STING1 (HGNC:27962): (stimulator of interferon response cGAMP interactor 1) This gene encodes a five transmembrane protein that functions as a major regulator of the innate immune response to viral and bacterial infections. The encoded protein is a pattern recognition receptor that detects cytosolic nucleic acids and transmits signals that activate type I interferon responses. The encoded protein has also been shown to play a role in apoptotic signaling by associating with type II major histocompatibility complex. Mutations in this gene are the cause of infantile-onset STING-associated vasculopathy. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

STING1 Gene-Disease associations (from GenCC):

STING-associated vasculopathy with onset in infancy
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
familial chilblain lupus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

STING1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_198282.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-139480847-C-T is Pathogenic according to our data. Variant chr5-139480847-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 143862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STING1	NM_198282.4 link	c.463G>A	p.Val155Met	missense_variant	Exon 5 of 8	ENST00000330794.9	NP_938023.1	Q86WV6
STING1	NM_001301738.2 link	c.463G>A	p.Val155Met	missense_variant	Exon 5 of 7		NP_001288667.1	J3QTB1V5V0K2
STING1	NM_001367258.1 link	c.106G>A	p.Val36Met	missense_variant	Exon 4 of 7		NP_001354187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STING1	ENST00000330794.9 link	c.463G>A	p.Val155Met	missense_variant	Exon 5 of 8	1	NM_198282.4	ENSP00000331288.4		Q86WV6

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251308

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41434

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000267

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

STING-associated vasculopathy with onset in infancy

Pathogenic:5

Dec 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with STING-associated vasculopathy, infantile-onset (MIM#615934). Missense variants were shown to result in reporter activation (PMID: 25029335). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported (PMID: 25401470). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3 and v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants, within the connecter helix loop (DECIPHER, PMID: 32673614). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in at least five unrelated individuals with an inflammatory syndrome or infantile onset interstitial lung disease. In four of these individuals, the variant was found to be de novo (ClinVar, PMID: 25029335, PMID: 25401470, PMID: 31705453). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant segregated in three affected members of a single family with a familial inflammatory syndrome (PMID: 25401470). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells showed elevated transcription of IFNB1 and other gene targets (PMID: 25029335, PMID: 25401470). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2022

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 155 of the TMEM173 protein (p.Val155Met). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with STING-associated vasculopathy (SAVI) and severe pulmonary disease (PMID: 25029335, 25401470, 27613991). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143862). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM173 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TMEM173 function (PMID: 25029335, 25401470, 26235147, 28484079). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

STING1: PM6:Strong, PP1:Strong, PM2, PS4:Moderate, PS3:Supporting -

Aug 13, 2015

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The V155M substitution in the TMEM173 gene has been reported previously as both a de novo variant andin a family with multiple affected individuals showing variable clinical features consistent with SALVI (Liuet al., 2014; Jeremiah et al., 2014). Functional studies of the V155M variant indicate it results in gain offunction upregulation of type I interferon production (Jeremiah, et al., 2014). The V155M variant was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The V155Mvariant is a conservative amino acid substitution, which is at a position that is conserved, but Methioninehas been observed at this position in evolution. In silico analysis predicts this variant is probably damagingto the protein structure/function. Missense variants in nearby residues (V147L and N154S) have beenreported in the Human Gene Mutation Database in association with early onset vasculopathy (Stenson etal., 2014), supporting the functional importance of this region of the protein. We interpret V155M as a pathogenic variant. -

Nov 22, 2021

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMEM173 NM_198282 exon 5 p.Val155Met (c.463G>A): This variant has been reported in the literature in at least 4 individuals with suspected STING related disease (early onset systemic inflammation, cutaneous vasculopathy and pulmonary inflammation), segregating with disease in 2 affected family members and identified as de novo in 2 individuals (Jeremiah 2014 PMID:25401470, Liu 2014 PMID:25029335, Picard 2016 PMID:27613991). This variant is present in 1/15300 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID:143862). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies also predict that this variant will impact the protein, with authors proposing a gain of function mechanism (Jeremiah 2014 PMID:25401470, Liu 2014 PMID:25029335, Cerboni 2017 PMID:28484079). In summary, this variant is classified as pathogenic based on the data above. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

D;.

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.8

M;.

PhyloP100

2.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.6

N;N

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.47

Loss of catalytic residue at V155 (P = 0.0024);Loss of catalytic residue at V155 (P = 0.0024);

MVP

0.75

MPC

1.2

ClinPred

0.97

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.65

Mutation Taster

=22/78

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over