NM_001111.5:c.298A>G

Variant names:

• chr1-154602344-T-C
• rs1466731
• NM_001111.5:c.298A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001111.5(ADAR):​c.298A>G​(p.Arg100Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,609,886 control chromosomes in the GnomAD database, including 803,673 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 1.0 (75598 hom., cov: 32)
  • Exomes 𝑓: 1.0 (728075 hom.)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.23
• Publications: 30 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1511453E-6).
• BP6: Variant 1-154602344-T-C is Benign according to our data. Variant chr1-154602344-T-C is described in ClinVar as Benign. ClinVar VariationId is 500335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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.298A>G	p.Arg100Gly	missense	Exon 2 of 15	NP_001102.3	P55265-1
	ADAR	NM_001365045.1		c.325A>G	p.Arg109Gly	missense	Exon 2 of 15	NP_001351974.1
	ADAR	NM_015840.4		c.298A>G	p.Arg100Gly	missense	Exon 2 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.298A>G	p.Arg100Gly	missense	Exon 2 of 15	ENSP00000357459.4	P55265-1
	ADAR	ENST00000368471.8	TSL:1	c.-588A>G		5_prime_UTR	Exon 2 of 15	ENSP00000357456.3	P55265-5
	ADAR	ENST00000649724.2		c.328A>G	p.Arg110Gly	missense	Exon 2 of 15	ENSP00000497932.2	A0AAG2TPY2

Frequencies

GnomAD3 genomes AF: 0.996 AC: 151639 AN: 152204 Hom.: 75542 Cov.: 32

Gnomad AFR AF: 0.987

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.998

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.996

GnomAD2 exomes AF: 0.999 AC: 247457 AN: 247740 AF XY: 0.999

Gnomad AFR exome AF: 0.985

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1456845 AN: 1457564 Hom.: 728075 Cov.: 81 AF XY: 1.00 AC XY: 724735 AN XY: 725054

African (AFR) AF: 0.983 AC: 32836 AN: 33394

American (AMR) AF: 0.999 AC: 44316 AN: 44356

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25660 AN: 25660

East Asian (EAS) AF: 1.00 AC: 39688 AN: 39688

South Asian (SAS) AF: 1.00 AC: 85605 AN: 85614

European-Finnish (FIN) AF: 1.00 AC: 53210 AN: 53210

Middle Eastern (MID) AF: 0.998 AC: 5735 AN: 5746

European-Non Finnish (NFE) AF: 1.00 AC: 1109681 AN: 1109700

Other (OTH) AF: 0.999 AC: 60114 AN: 60196

GnomAD4 genome AF: 0.996 AC: 151755 AN: 152322 Hom.: 75598 Cov.: 32 AF XY: 0.996 AC XY: 74206 AN XY: 74474

African (AFR) AF: 0.987 AC: 41054 AN: 41584

American (AMR) AF: 0.998 AC: 15286 AN: 15310

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5164 AN: 5164

South Asian (SAS) AF: 1.00 AC: 4818 AN: 4820

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68032 AN: 68032

Other (OTH) AF: 0.996 AC: 2105 AN: 2114

Alfa AF: 0.998 Hom.: 136918

Bravo AF: 0.995

TwinsUK AF: 1.00 AC: 3707

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.988 AC: 4351

ESP6500EA AF: 1.00 AC: 8599

ExAC AF: 0.999 AC: 121246

Asia WGS AF: 1.00 AC: 3477 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 (2)
-	-	1	Aicardi-Goutieres syndrome 6 (1)
-	-	1	not provided (1)
-	-	1	Symmetrical dyschromatosis of extremities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.27
DANN	Benign	0.11
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-1.2
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.0080
Sift	Benign	0.81	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.31
ClinPred		0.00041	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.058
gMVP		0.29
Mutation Taster		=98/2	polymorphism (auto)

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: rs1466731; hg19: chr1-154574820; COSMIC: COSV107345044;