rs398122892

Variant names:

• chr1-154589456-C-T
• rs398122892
• NM_001111.5:c.2675G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001111.5(ADAR):​c.2675G>A​(p.Arg892His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R892R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 5.48
• Publications: 15 publications found

Genes affected

ADAR (HGNC:225): (adenosine deaminase RNA specific) This gene encodes the enzyme responsible for RNA editing by site-specific deamination of adenosines. This enzyme destabilizes double-stranded RNA through conversion of adenosine to inosine. Mutations in this gene have been associated with dyschromatosis symmetrica hereditaria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

ADAR Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 6

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyschromatosis symmetrica hereditaria

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• ADAR-related type 1 interferonopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial infantile bilateral striatal necrosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111.5. 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
	ADAR	NM_001111.5	MANE Select	c.2675G>A	p.Arg892His	missense	Exon 9 of 15	NP_001102.3	P55265-1
	ADAR	NM_001365045.1		c.2702G>A	p.Arg901His	missense	Exon 9 of 15	NP_001351974.1
	ADAR	NM_015840.4		c.2597G>A	p.Arg866His	missense	Exon 9 of 15	NP_056655.3	P55265-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAR	ENST00000368474.9	TSL:1 MANE Select	c.2675G>A	p.Arg892His	missense	Exon 9 of 15	ENSP00000357459.4	P55265-1
	ADAR	ENST00000368471.8	TSL:1	c.1790G>A	p.Arg597His	missense	Exon 9 of 15	ENSP00000357456.3	P55265-5
	ADAR	ENST00000649724.2		c.2705G>A	p.Arg902His	missense	Exon 9 of 15	ENSP00000497932.2	A0AAG2TPY2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251106 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000274 AC: 4 AN: 1459864 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726418

African (AFR) AF: 0.0000299 AC: 1 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110272

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Aicardi-Goutieres syndrome 6 (2)
-	1	-	Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.80		Loss of sheet (P = 0.0315)
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.85
gMVP		0.82
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398122892; hg19: chr1-154561932; COSMIC: COSV52716474; COSMIC: COSV52716474;