dbSNP rs587777611: STING1:p.Val147Leu (chr5-139480871-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP5BP4

The NM_198282.4(STING1):c.439G>C(p.Val147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V147M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

STING1
NM_198282.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -0.487

Publications

66 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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, 4 uncertain in NM_198282.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-139480871-C-G is Pathogenic according to our data. Variant chr5-139480871-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 143863.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.11408475). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198282.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STING1	NM_198282.4	MANE Select	c.439G>C	p.Val147Leu	missense	Exon 5 of 8	NP_938023.1
STING1	NM_001301738.2		c.439G>C	p.Val147Leu	missense	Exon 5 of 7	NP_001288667.1
STING1	NM_001367258.1		c.82G>C	p.Val28Leu	missense	Exon 4 of 7	NP_001354187.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STING1	ENST00000330794.9	TSL:1 MANE Select	c.439G>C	p.Val147Leu	missense	Exon 5 of 8	ENSP00000331288.4
STING1	ENST00000512606.6	TSL:1	n.675G>C		non_coding_transcript_exon	Exon 3 of 6
STING1	ENST00000651699.1		c.439G>C	p.Val147Leu	missense	Exon 4 of 7	ENSP00000499166.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

STING-associated vasculopathy with onset in infancy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.4

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.039

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.7

PhyloP100

-0.49

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.050

REVEL

Pathogenic

0.65

Sift

Benign

0.39

Sift4G

Benign

0.38

Polyphen

0.018

Vest4

0.70

MutPred

0.28

Loss of methylation at K150 (P = 0.1359)

MVP

0.15

MPC

0.51

ClinPred

0.059

GERP RS

-5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over