5-139476277-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198282.4(STING1):c.1124G>T(p.Arg375Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00036 in 1,588,738 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R375H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (5 hom.)
• Consequence: STING1 NM_198282.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.05

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=0.0076682866).
• BP6: Variant 5-139476277-C-A is Benign according to our data. Variant chr5-139476277-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 719130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000296 (45/152192) while in subpopulation EAS AF= 0.00774 (40/5168). AF 95% confidence interval is 0.00584. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STING1	NM_198282.4	c.1124G>T	p.Arg375Leu	missense_variant	8/8	ENST00000330794.9
STING1	NM_001367258.1	c.767G>T	p.Arg256Leu	missense_variant	7/7
STING1	NM_001301738.2	c.*85G>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STING1	ENST00000330794.9	c.1124G>T	p.Arg375Leu	missense_variant	8/8	1	NM_198282.4	P1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152074 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00792

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000784 AC: 167 AN: 213096 Hom.: 2 AF XY: 0.000681 AC XY: 78 AN XY: 114454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0102

Gnomad SAS exome AF: 0.0000737

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000431

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000367 AC: 527 AN: 1436546 Hom.: 5 Cov.: 31 AF XY: 0.000363 AC XY: 259 AN XY: 712626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000149

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0117

Gnomad4 SAS exome AF: 0.000156

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.0000155

Gnomad4 OTH exome AF: 0.000674

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.000403 AC XY: 30 AN XY: 74420

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00774

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000498 Hom.: 2

Bravo AF: 0.000280

ExAC AF: 0.000735 AC: 89

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

STING-associated vasculopathy with onset in infancy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 13, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.069
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	0.91	D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.10
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.49
MPC		1.5
ClinPred		0.21	T
GERP RS		3.5
Varity_R		0.53

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: rs117897081; hg19: chr5-138855862;