rs587777611

Variant names:

• chr5-139480871-C-G
• rs587777611
• NM_198282.4:c.439G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.487
• Publications: 66 publications found

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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STING1	NM_198282.4	c.439G>C	p.Val147Leu	missense_variant	Exon 5 of 8	ENST00000330794.9	NP_938023.1
STING1	NM_001301738.2	c.439G>C	p.Val147Leu	missense_variant	Exon 5 of 7		NP_001288667.1
STING1	NM_001367258.1	c.82G>C	p.Val28Leu	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	c.439G>C	p.Val147Leu	missense_variant	Exon 5 of 8	1	NM_198282.4	ENSP00000331288.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

STING-associated vasculopathy with onset in infancy Pathogenic:1

Aug 07, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.4
DANN	Benign	0.48
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.72	T;.
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		-0.49
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.050	N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.39	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.018	B;.
Vest4		0.70
MutPred		0.28		Loss of methylation at K150 (P = 0.1359);Loss of methylation at K150 (P = 0.1359);
MVP		0.15
MPC		0.51
ClinPred		0.059	T
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)

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

Other links and lift over

dbSNP: rs587777611; hg19: chr5-138860456;