5-139476373-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198282.4(STING1):c.1028T>C(p.Val343Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V343M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: STING1 NM_198282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18253249).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STING1	NM_198282.4	c.1028T>C	p.Val343Ala	missense_variant	8/8	ENST00000330794.9
STING1	NM_001301738.2	c.841T>C	p.Trp281Arg	missense_variant	7/7
STING1	NM_001367258.1	c.671T>C	p.Val224Ala	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STING1	ENST00000330794.9	c.1028T>C	p.Val343Ala	missense_variant	8/8	1	NM_198282.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460506 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726552

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

STING-associated vasculopathy with onset in infancy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 21, 2023

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 343 of the TMEM173 protein (p.Val343Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TMEM173-related conditions. 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.073
Sift	Benign	0.030	D
Sift4G	Uncertain	0.059	T
Polyphen		0.87	P
Vest4		0.11
MutPred		0.20		Gain of helix (P = 0.0128);
MVP		0.51
MPC		0.82
ClinPred		0.44	T
GERP RS		5.2
Varity_R		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1751659620; hg19: chr5-138855958;