5-139476325-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198282.4(STING1):c.1076A>G(p.Gln359Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,611,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q359Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000033 (2 hom.)
• Consequence: STING1 NM_198282.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.0590

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01511097).
• BP6: Variant 5-139476325-T-C is Benign according to our data. Variant chr5-139476325-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 641434.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000217 (33/152204) while in subpopulation AFR AF= 0.000698 (29/41540). AF 95% confidence interval is 0.000499. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STING1	NM_198282.4	c.1076A>G	p.Gln359Arg	missense_variant	8/8	ENST00000330794.9
STING1	NM_001367258.1	c.719A>G	p.Gln240Arg	missense_variant	7/7
STING1	NM_001301738.2	c.*37A>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STING1	ENST00000330794.9	c.1076A>G	p.Gln359Arg	missense_variant	8/8	1	NM_198282.4	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000642 AC: 16 AN: 249354 Hom.: 0 AF XY: 0.0000594 AC XY: 8 AN XY: 134754

Gnomad AFR exome AF: 0.000619

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000329 AC: 48 AN: 1459758 Hom.: 2 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 726074

Gnomad4 AFR exome AF: 0.000927

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74432

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000814 Hom.: 0

Bravo AF: 0.000257

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

The c.1076A>G (p.Q359R) alteration is located in exon 8 (coding exon 6) of the TMEM173 gene. This alteration results from a A to G substitution at nucleotide position 1076, causing the glutamine (Q) at amino acid position 359 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

STING-associated vasculopathy with onset in infancy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2023

This variant has not been reported in the literature in individuals affected with TMEM173-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 641434). This variant is present in population databases (rs141830680, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 359 of the TMEM173 protein (p.Gln359Arg). -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.11
Sift	Benign	0.30	T
Sift4G	Benign	0.37	T
Polyphen		0.43	B
Vest4		0.10
MVP		0.39
MPC		0.61
ClinPred		0.014	T
GERP RS		4.0
Varity_R		0.14

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: rs141830680; hg19: chr5-138855910;