rs1131769

Positions:

• chr5-139478334-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198282.4(STING1):​c.695A>G​(p.His232Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 1,613,916 control chromosomes in the GnomAD database, including 615,846 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 0.87 (57719 hom., cov: 31)
  • Exomes 𝑓: 0.87 (558127 hom.)
• Consequence: STING1 NM_198282.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 2.21

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=1.4088237E-6).
• BP6: Variant 5-139478334-T-C is Benign according to our data. Variant chr5-139478334-T-C is described in ClinVar as [Benign]. Clinvar id is 403550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STING1	NM_198282.4	c.695A>G	p.His232Arg	missense_variant	6/8	ENST00000330794.9	NP_938023.1
STING1	NM_001301738.2	c.695A>G	p.His232Arg	missense_variant	6/7		NP_001288667.1
STING1	NM_001367258.1	c.338A>G	p.His113Arg	missense_variant	5/7		NP_001354187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STING1	ENST00000330794.9	c.695A>G	p.His232Arg	missense_variant	6/8	1	NM_198282.4	ENSP00000331288	P1

Frequencies

GnomAD3 genomes AF: 0.871 AC: 132374 AN: 151992 Hom.: 57673 Cov.: 31

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.755

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.881

Gnomad SAS AF: 0.905

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.874

GnomAD3 exomes AF: 0.876 AC: 220195 AN: 251454 Hom.: 96547 AF XY: 0.875 AC XY: 118967 AN XY: 135902

Gnomad AFR exome AF: 0.882

Gnomad AMR exome AF: 0.887

Gnomad ASJ exome AF: 0.855

Gnomad EAS exome AF: 0.880

Gnomad SAS exome AF: 0.907

Gnomad FIN exome AF: 0.864

Gnomad NFE exome AF: 0.866

Gnomad OTH exome AF: 0.877

GnomAD4 exome AF: 0.874 AC: 1276983 AN: 1461806 Hom.: 558127 Cov.: 62 AF XY: 0.874 AC XY: 635860 AN XY: 727206

Gnomad4 AFR exome AF: 0.890

Gnomad4 AMR exome AF: 0.885

Gnomad4 ASJ exome AF: 0.854

Gnomad4 EAS exome AF: 0.873

Gnomad4 SAS exome AF: 0.909

Gnomad4 FIN exome AF: 0.864

Gnomad4 NFE exome AF: 0.871

Gnomad4 OTH exome AF: 0.874

GnomAD4 genome AF: 0.871 AC: 132478 AN: 152110 Hom.: 57719 Cov.: 31 AF XY: 0.869 AC XY: 64615 AN XY: 74332

Gnomad4 AFR AF: 0.881

Gnomad4 AMR AF: 0.857

Gnomad4 ASJ AF: 0.855

Gnomad4 EAS AF: 0.882

Gnomad4 SAS AF: 0.905

Gnomad4 FIN AF: 0.857

Gnomad4 NFE AF: 0.869

Gnomad4 OTH AF: 0.875

Alfa AF: 0.866 Hom.: 105611

Bravo AF: 0.871

TwinsUK AF: 0.867 AC: 3213

ALSPAC AF: 0.865 AC: 3332

ESP6500AA AF: 0.872 AC: 3841

ESP6500EA AF: 0.869 AC: 7475

ExAC AF: 0.876 AC: 106354

Asia WGS AF: 0.873 AC: 3037 AN: 3478

EpiCase AF: 0.866

EpiControl AF: 0.862

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

STING-associated vasculopathy with onset in infancy Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 14, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported. -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 23707065, 24204993, 33154747, 31866997) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.22
DEOGEN2	Benign	0.066	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.26	T;.
MetaRNN	Benign	0.0000014	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.8	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	4.5	N;N
REVEL	Benign	0.083
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.036
MPC		0.58
ClinPred		0.0023	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1131769; hg19: chr5-138857919;