1-154598427-T-C

Variant names:

• chr1-154598427-T-C
• rs17843865
• NM_001111.5:c.1760A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001111.5(ADAR):​c.1760A>G​(p.Tyr587Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,614,182 control chromosomes in the GnomAD database, including 39 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y587S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0099 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (15 hom.)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.767
• Publications: 16 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=0.0025766492).
• BP6: Variant 1-154598427-T-C is Benign according to our data. Variant chr1-154598427-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196312.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 = 0.00986 (1501/152300) while in subpopulation AFR AF = 0.0325 (1350/41554). AF 95% confidence interval is 0.031. There are 24 homozygotes in GnomAd4. There are 683 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AD,AR gene

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.1760A>G	p.Tyr587Cys	missense	Exon 3 of 15	NP_001102.3	P55265-1
	ADAR	NM_001365045.1		c.1787A>G	p.Tyr596Cys	missense	Exon 3 of 15	NP_001351974.1
	ADAR	NM_015840.4		c.1760A>G	p.Tyr587Cys	missense	Exon 3 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.1760A>G	p.Tyr587Cys	missense	Exon 3 of 15	ENSP00000357459.4	P55265-1
	ADAR	ENST00000368471.8	TSL:1	c.875A>G	p.Tyr292Cys	missense	Exon 3 of 15	ENSP00000357456.3	P55265-5
	ADAR	ENST00000649724.2		c.1790A>G	p.Tyr597Cys	missense	Exon 3 of 15	ENSP00000497932.2	A0AAG2TPY2

Frequencies

GnomAD3 genomes AF: 0.00984 AC: 1497 AN: 152182 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00361 AC: 907 AN: 251430 AF XY: 0.00282

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0126

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00131 AC: 1913 AN: 1461882 Hom.: 15 Cov.: 32 AF XY: 0.00114 AC XY: 828 AN XY: 727246

African (AFR) AF: 0.0339 AC: 1136 AN: 33476

American (AMR) AF: 0.00215 AC: 96 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00771 AC: 306 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.000106 AC: 118 AN: 1112006

Other (OTH) AF: 0.00381 AC: 230 AN: 60396

GnomAD4 genome AF: 0.00986 AC: 1501 AN: 152300 Hom.: 24 Cov.: 32 AF XY: 0.00917 AC XY: 683 AN XY: 74482

African (AFR) AF: 0.0325 AC: 1350 AN: 41554

American (AMR) AF: 0.00398 AC: 61 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0125 AC: 65 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68012

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00373 Hom.: 18

Bravo AF: 0.0108

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00418 AC: 508

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Aicardi-Goutieres syndrome 6 (1)
-	-	1	not specified (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	0.063
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.96
DANN	Benign	0.58
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.060	N
PhyloP100		-0.77
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.0030
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.083
MVP		0.093
MPC		0.30
ClinPred		0.00013	T
GERP RS		-6.4
Varity_R		0.032
gMVP		0.21
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs17843865; hg19: chr1-154570903; COSMIC: COSV52713039; COSMIC: COSV52713039;