rs114834699

chr5-139478449-C-A

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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

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 Benign. Variant got -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 id is 475209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-139478449-C-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 524 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STING1	NM_198282.4	c.580G>T	p.Val194Leu	missense_variant	6/8	ENST00000330794.9
STING1	NM_001301738.2	c.580G>T	p.Val194Leu	missense_variant	6/7
STING1	NM_001367258.1	c.223G>T	p.Val75Leu	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STING1	ENST00000330794.9	c.580G>T	p.Val194Leu	missense_variant	6/8	1	NM_198282.4	P1

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

GnomAD3 exomes AF: 0.00124 AC: 313 AN: 251486 Hom.: 2 AF XY: 0.00110 AC XY: 150 AN XY: 135916

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.00192

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

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000707 Hom.: 0

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2024

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

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

STING1: BP4, BS1, BS2 -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 05, 2021

- -

STING-associated vasculopathy with onset in infancy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.055
Sift	Benign	0.34	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.011	B;.
Vest4		0.061
MutPred		0.30		Loss of sheet (P = 0.1158);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

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

Other links and lift over

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