rs140837017

chr5-139477338-C-T

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.937G>A(p.Ala313Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,613,772 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A313V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0073 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (19 hom.)
• Consequence: STING1 NM_198282.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.83

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=0.008134723).
• BP6: Variant 5-139477338-C-T is Benign according to our data. Variant chr5-139477338-C-T is described in ClinVar as [Benign]. Clinvar id is 475211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00729 (1110/152322) while in subpopulation AFR AF= 0.021 (875/41580). AF 95% confidence interval is 0.0199. There are 16 homozygotes in gnomad4. There are 526 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STING1	NM_198282.4	c.937G>A	p.Ala313Thr	missense_variant	7/8	ENST00000330794.9
STING1	NM_001367258.1	c.580G>A	p.Ala194Thr	missense_variant	6/7
STING1	NM_001301738.2	c.760-884G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STING1	ENST00000330794.9	c.937G>A	p.Ala313Thr	missense_variant	7/8	1	NM_198282.4	P1

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 1110 AN: 152204 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00911

GnomAD3 exomes AF: 0.00303 AC: 759 AN: 250120 Hom.: 6 AF XY: 0.00271 AC XY: 367 AN XY: 135394

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.00679

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00176 AC: 2572 AN: 1461450 Hom.: 19 Cov.: 31 AF XY: 0.00176 AC XY: 1283 AN XY: 726982

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.00559

Gnomad4 ASJ exome AF: 0.00728

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000789

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.000868

Gnomad4 OTH exome AF: 0.00467

GnomAD4 genome AF: 0.00729 AC: 1110 AN: 152322 Hom.: 16 Cov.: 32 AF XY: 0.00706 AC XY: 526 AN XY: 74478

Gnomad4 AFR AF: 0.0210

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.00225 Hom.: 2

Bravo AF: 0.00814

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0172 AC: 76

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00333 AC: 404

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00219

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 28, 2022

- -

STING-associated vasculopathy with onset in infancy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.034
Sift	Benign	0.16	T
Sift4G	Uncertain	0.049	D
Polyphen		0.010	B
Vest4		0.14
MVP		0.21
MPC		0.46
ClinPred		0.013	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.19

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: rs140837017; hg19: chr5-138856923;