chr5-139480847-C-T

Position:

chr5-139480847-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The ENST00000330794.9(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
ENST00000330794.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.64

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 ENST00000330794.9

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 id is 143862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-139480847-C-T is described in UniProt as null. Variant chr5-139480847-C-T is described in UniProt as null. Variant chr5-139480847-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
STING1	NM_198282.4 linkuse as main transcript	c.463G>A	p.Val155Met	missense_variant	5/8	ENST00000330794.9	NP_938023.1
STING1	NM_001301738.2 linkuse as main transcript	c.463G>A	p.Val155Met	missense_variant	5/7		NP_001288667.1
STING1	NM_001367258.1 linkuse as main transcript	c.106G>A	p.Val36Met	missense_variant	4/7		NP_001354187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STING1	ENST00000330794.9 linkuse as main transcript	c.463G>A	p.Val155Met	missense_variant	5/8	1	NM_198282.4	ENSP00000331288	P1

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251308

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135828

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

STING-associated vasculopathy with onset in infancy

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TMEM173 function (PMID: 25029335, 25401470, 26235147, 28484079). 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. ClinVar contains an entry for this variant (Variation ID: 143862). 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. This variant is present in population databases (no rsID available, gnomAD 0.007%). 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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2015	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 22, 2021	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

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;.

MutationTaster

Benign

1.0

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

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