chr5-139478449-C-A

Variant names:

• chr5-139478449-C-A
• rs114834699
• NM_198282.4:c.580G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198282.4(STING1):​c.580G>T​(p.Val194Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 1,614,222 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00063 (12 hom.)
• Consequence: STING1 NM_198282.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.971
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005369246).
• BP6: Variant 5-139478449-C-A is Benign according to our data. Variant chr5-139478449-C-A is described in ClinVar as Benign. ClinVar VariationId is 475209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00345 (525/152332) while in subpopulation AFR AF = 0.0105 (435/41576). AF 95% confidence interval is 0.00965. There are 5 homozygotes in GnomAd4. There are 250 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 525 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STING1	NM_198282.4	MANE Select	c.580G>T	p.Val194Leu	missense	Exon 6 of 8	NP_938023.1
	STING1	NM_001301738.2		c.580G>T	p.Val194Leu	missense	Exon 6 of 7	NP_001288667.1
	STING1	NM_001367258.1		c.223G>T	p.Val75Leu	missense	Exon 5 of 7	NP_001354187.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STING1	ENST00000330794.9	TSL:1 MANE Select	c.580G>T	p.Val194Leu	missense	Exon 6 of 8	ENSP00000331288.4
	STING1	ENST00000512606.6	TSL:1	n.816G>T		non_coding_transcript_exon	Exon 4 of 6
	STING1	ENST00000651699.1		c.580G>T	p.Val194Leu	missense	Exon 5 of 7	ENSP00000499166.1

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 524 AN: 152214 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00124 AC: 313 AN: 251486 AF XY: 0.00110

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000635 AC: 928 AN: 1461890 Hom.: 12 Cov.: 34 AF XY: 0.000645 AC XY: 469 AN XY: 727248

African (AFR) AF: 0.0145 AC: 485 AN: 33480

American (AMR) AF: 0.00168 AC: 75 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.000169 AC: 188 AN: 1112008

Other (OTH) AF: 0.00192 AC: 116 AN: 60396

GnomAD4 genome AF: 0.00345 AC: 525 AN: 152332 Hom.: 5 Cov.: 31 AF XY: 0.00336 AC XY: 250 AN XY: 74492

African (AFR) AF: 0.0105 AC: 435 AN: 41576

American (AMR) AF: 0.00418 AC: 64 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00125 Hom.: 1

Bravo AF: 0.00392

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00137 AC: 167

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

STING1-related disorder Benign:1

Jan 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STING1: BP4, BS1, BS2

Autoinflammatory syndrome Benign:1

Apr 05, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STING-associated vasculopathy with onset in infancy Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.3
DANN	Benign	0.74
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.97
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.055
Sift	Benign	0.34	T
Sift4G	Benign	0.31	T
Polyphen		0.011	B
Vest4		0.061
MutPred		0.30		Loss of sheet (P = 0.1158)
MVP		0.22
MPC		0.48
ClinPred		0.0010	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs114834699; hg19: chr5-138858034; COSMIC: COSV99043783; COSMIC: COSV99043783;