5-139476272-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_198282.4(STING1):c.1129G>T(p.Asp377Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000699 in 1,431,144 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: STING1 NM_198282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23

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 2 ACMG points.

• PM1: In a mutagenesis_site Does not affect ability to activate IRF3. (size 0) in uniprot entity STING_HUMAN

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STING1	NM_198282.4	c.1129G>T	p.Asp377Tyr	missense_variant	8/8	ENST00000330794.9
STING1	NM_001367258.1	c.772G>T	p.Asp258Tyr	missense_variant	7/7
STING1	NM_001301738.2	c.*90G>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STING1	ENST00000330794.9	c.1129G>T	p.Asp377Tyr	missense_variant	8/8	1	NM_198282.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000699 AC: 10 AN: 1431144 Hom.: 0 Cov.: 31 AF XY: 0.00000705 AC XY: 5 AN XY: 709556

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: 0.00000911

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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 17, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 377 of the TMEM173 protein (p.Asp377Tyr). 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. ClinVar contains an entry for this variant (Variation ID: 945312). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.054
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.31		Gain of catalytic residue at D377 (P = 0.0376);
MVP		0.53
MPC		1.5
ClinPred		0.87	D
GERP RS		4.5
Varity_R		0.44

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: rs1368968919; hg19: chr5-138855857;