NM_001111.5:c.1151A>G

Variant names:

• chr1-154601491-T-C
• rs2229857
• NM_001111.5:c.1151A>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.1151A>G​(p.Lys384Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 1,613,916 control chromosomes in the GnomAD database, including 390,071 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31054 hom., cov: 32)
  • Exomes 𝑓: 0.70 (359017 hom.)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.324
• Publications: 73 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=1.1812625E-6).
• BP6: Variant 1-154601491-T-C is Benign according to our data. Variant chr1-154601491-T-C is described in ClinVar as Benign. ClinVar VariationId is 195112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.747 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.1151A>G	p.Lys384Arg	missense	Exon 2 of 15	NP_001102.3	P55265-1
	ADAR	NM_001365045.1		c.1178A>G	p.Lys393Arg	missense	Exon 2 of 15	NP_001351974.1
	ADAR	NM_015840.4		c.1151A>G	p.Lys384Arg	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.1151A>G	p.Lys384Arg	missense	Exon 2 of 15	ENSP00000357459.4	P55265-1
	ADAR	ENST00000368471.8	TSL:1	c.266A>G	p.Lys89Arg	missense	Exon 2 of 15	ENSP00000357456.3	P55265-5
	ADAR	ENST00000649724.2		c.1181A>G	p.Lys394Arg	missense	Exon 2 of 15	ENSP00000497932.2	A0AAG2TPY2

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95137 AN: 152016 Hom.: 31043 Cov.: 32

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.730

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.706

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.644

GnomAD2 exomes AF: 0.703 AC: 176710 AN: 251442 AF XY: 0.705

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.817

Gnomad ASJ exome AF: 0.710

Gnomad EAS exome AF: 0.711

Gnomad FIN exome AF: 0.657

Gnomad NFE exome AF: 0.703

Gnomad OTH exome AF: 0.699

GnomAD4 exome AF: 0.699 AC: 1021224 AN: 1461782 Hom.: 359017 Cov.: 78 AF XY: 0.702 AC XY: 510715 AN XY: 727202

African (AFR) AF: 0.417 AC: 13949 AN: 33480

American (AMR) AF: 0.806 AC: 36042 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 18473 AN: 26134

East Asian (EAS) AF: 0.730 AC: 28967 AN: 39700

South Asian (SAS) AF: 0.760 AC: 65555 AN: 86256

European-Finnish (FIN) AF: 0.664 AC: 35408 AN: 53346

Middle Eastern (MID) AF: 0.719 AC: 4147 AN: 5768

European-Non Finnish (NFE) AF: 0.699 AC: 777599 AN: 1111980

Other (OTH) AF: 0.680 AC: 41084 AN: 60394

GnomAD4 genome AF: 0.626 AC: 95169 AN: 152134 Hom.: 31054 Cov.: 32 AF XY: 0.630 AC XY: 46865 AN XY: 74386

African (AFR) AF: 0.420 AC: 17405 AN: 41468

American (AMR) AF: 0.730 AC: 11167 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 2506 AN: 3466

East Asian (EAS) AF: 0.706 AC: 3657 AN: 5182

South Asian (SAS) AF: 0.768 AC: 3698 AN: 4818

European-Finnish (FIN) AF: 0.652 AC: 6900 AN: 10586

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.701 AC: 47674 AN: 68002

Other (OTH) AF: 0.638 AC: 1351 AN: 2116

Alfa AF: 0.683 Hom.: 173537

Bravo AF: 0.623

TwinsUK AF: 0.705 AC: 2614

ALSPAC AF: 0.693 AC: 2669

ESP6500AA AF: 0.429 AC: 1888

ESP6500EA AF: 0.700 AC: 6018

ExAC AF: 0.696 AC: 84446

Asia WGS AF: 0.697 AC: 2425 AN: 3478

EpiCase AF: 0.704

EpiControl AF: 0.697

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (3)
-	-	2	Symmetrical dyschromatosis of extremities (2)
-	-	1	Aicardi-Goutieres syndrome 6 (1)
-	-	1	Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.18
DANN	Benign	0.94
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.32
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.012
Sift	Benign	0.38	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.20
ClinPred		0.0030	T
GERP RS		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.017
gMVP		0.072
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: rs2229857; hg19: chr1-154573967; COSMIC: COSV107345043; COSMIC: COSV107345043;