rs201096097

chr5-139478454-C-Achr5-139478454-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_198282.4(STING1):c.575G>T(p.Gly192Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,614,210 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G192D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: STING1 NM_198282.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 0.312

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 -9 ACMG points.

• BP6: Variant 5-139478454-C-A is Benign according to our data. Variant chr5-139478454-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475208.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr5-139478454-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000171 (26/152322) while in subpopulation SAS AF= 0.000621 (3/4830). AF 95% confidence interval is 0.000169. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STING1	NM_198282.4	c.575G>T	p.Gly192Val	missense_variant	6/8	ENST00000330794.9
STING1	NM_001301738.2	c.575G>T	p.Gly192Val	missense_variant	6/7
STING1	NM_001367258.1	c.218G>T	p.Gly73Val	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STING1	ENST00000330794.9	c.575G>T	p.Gly192Val	missense_variant	6/8	1	NM_198282.4	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000266 AC: 67 AN: 251474 Hom.: 1 AF XY: 0.000397 AC XY: 54 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000222 AC: 324 AN: 1461888 Hom.: 1 Cov.: 34 AF XY: 0.000274 AC XY: 199 AN XY: 727246

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000684

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152322 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74490

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000207 Hom.: 0

Bravo AF: 0.000208

ExAC AF: 0.000321 AC: 39

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	STING1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

STING-associated vasculopathy with onset in infancy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 192 of the TMEM173 protein (p.Gly192Val). This variant is present in population databases (rs201096097, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with disorders of immunity (PMID: 35086391, 35482138). ClinVar contains an entry for this variant (Variation ID: 475208). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 29, 2021	STING1 c.575G>T (rs201096097) is rare (<0.1%) in a large population dataset (gnomAD: 73/282854 total alleles; 0.03%; 1 homozygote) and has not been reported in the literature, to our knowledge. There is an entry for this variant in ClinVar (Variation ID: 475208). Of three bioinformatics tools queried, one predicts that the substitution would be possibly damaging, while two predict that it would be tolerated. The glycine at this position is conserved in most mammals, but not in the other species assessed. We consider the clinical significance of c.575G>T to be uncertain at this time. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.575G>T (p.G192V) alteration is located in exon 6 (coding exon 4) of the TMEM173 gene. This alteration results from a G to T substitution at nucleotide position 575, causing the glycine (G) at amino acid position 192 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

STING1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2023

The STING1 c.575G>T variant is predicted to result in the amino acid substitution p.Gly192Val. To our knowledge, this variant has not been reported in the literature in association with STING1 (TMEM173)-related disease but has been reported in individuals with early-onset systemic lupus erythematosus (Dasdemir et al. 2022. PubMed ID: 35086391), inborn errors of immunity (El Hawary et al. 2022. PubMed ID: 35482138), and autism spectrum disorder (Tuncay et al. 2023. PubMed ID: 37492102). This variant is reported in 0.065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-138858039-C-A). Although we suspect that this variant may be benign, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence. -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	13
Dann	Benign	0.90
DEOGEN2	Benign	0.063	T;.
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.66	T;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.16	N;N
REVEL	Benign	0.20
Sift	Benign	0.13	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.97	D;.
Vest4		0.26
MVP		0.48
MPC		1.3
ClinPred		0.16	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201096097; hg19: chr5-138858039;