rs587777611

Positions:

• chr5-139480871-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• 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 id is 143863.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-139480871-C-G is described in UniProt as null. Variant chr5-139480871-C-G is described in UniProt as null. Variant chr5-139480871-C-G is described in UniProt as null.
• 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/exons	MANE	Protein	UniProt
STING1	NM_198282.4	c.439G>C	p.Val147Leu	missense_variant	5/8	ENST00000330794.9	NP_938023.1
STING1	NM_001301738.2	c.439G>C	p.Val147Leu	missense_variant	5/7		NP_001288667.1
STING1	NM_001367258.1	c.82G>C	p.Val28Leu	missense_variant	4/7		NP_001354187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STING1	ENST00000330794.9	c.439G>C	p.Val147Leu	missense_variant	5/8	1	NM_198282.4	ENSP00000331288	P1

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 07, 2014

- -

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;.
MutationTaster	Benign	1.0	N
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

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

LitVar

Other links and lift over

dbSNP: rs587777611; hg19: chr5-138860456;