rs144606267

Variant names:

• chr5-139476278-G-A
• rs144606267
• NM_198282.4:c.1123C>T
• STING1 p.Arg375Cys

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_198282.4(STING1):​c.1123C>T​(p.Arg375Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,591,046 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R375H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: STING1 NM_198282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.27
• Publications: 7 publications found

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]

STING1 Gene-Disease associations (from GenCC):

• STING-associated vasculopathy with onset in infancy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial chilblain lupus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198282.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STING1	NM_198282.4	MANE Select	c.1123C>T	p.Arg375Cys	missense	Exon 8 of 8	NP_938023.1	Q86WV6
	STING1	NM_001367258.1		c.766C>T	p.Arg256Cys	missense	Exon 7 of 7	NP_001354187.1	A0A494C0W5
	STING1	NM_001301738.2		c.*84C>T		3_prime_UTR	Exon 7 of 7	NP_001288667.1	J3QTB1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STING1	ENST00000330794.9	TSL:1 MANE Select	c.1123C>T	p.Arg375Cys	missense	Exon 8 of 8	ENSP00000331288.4	Q86WV6
	STING1	ENST00000512606.6	TSL:1	n.1359C>T		non_coding_transcript_exon	Exon 6 of 6
	STING1	ENST00000651699.1		c.1123C>T	p.Arg375Cys	missense	Exon 7 of 7	ENSP00000499166.1	Q86WV6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000185 AC: 4 AN: 216386 AF XY: 0.00

Gnomad AFR exome AF: 0.000211

Gnomad AMR exome AF: 0.0000331

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000188 AC: 27 AN: 1438894 Hom.: 0 Cov.: 31 AF XY: 0.0000126 AC XY: 9 AN XY: 713998

African (AFR) AF: 0.00 AC: 0 AN: 33036

American (AMR) AF: 0.0000245 AC: 1 AN: 40776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 38600

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83356

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52224

Middle Eastern (MID) AF: 0.000226 AC: 1 AN: 4428

European-Non Finnish (NFE) AF: 0.0000209 AC: 23 AN: 1101296

Other (OTH) AF: 0.00 AC: 0 AN: 59468

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000561 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	STING-associated vasculopathy with onset in infancy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.3
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.54
Mutation Taster		=69/31	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs144606267;

hg19: chr5-138855863;

COSMIC: COSV58173124;

COSMIC: COSV58173124;