1-154598427-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.767

Publications

16 publications found

Variant links:

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
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
dyschromatosis symmetrica hereditaria
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
Aicardi-Goutieres syndrome 6
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
familial infantile bilateral striatal necrosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ADAR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAR	NM_001111.5 link	c.1760A>G	p.Tyr587Cys	missense_variant	Exon 3 of 15	ENST00000368474.9	NP_001102.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAR	ENST00000368474.9 link	c.1760A>G	p.Tyr587Cys	missense_variant	Exon 3 of 15	1	NM_001111.5	ENSP00000357459.4

Frequencies

GnomAD3 genomes

AF:

0.00984

AC:

1497

AN:

152182

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00114

AC XY:

828

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0339

AC:

1136

AN:

33476

American (AMR)

AF:

0.00215

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00771

AC:

306

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000106

AC:

118

AN:

1112006

Other (OTH)

AF:

0.00381

AC:

230

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

120

239

359

478

598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00986

AC:

1501

AN:

152300

Hom.:

Cov.:

AF XY:

0.00917

AC XY:

683

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0325

AC:

1350

AN:

41554

American (AMR)

AF:

0.00398

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0125

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68012

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00373

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0352

AC:

155

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00418

AC:

508

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 04, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADAR: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 19, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24446047, 32593192, 27884173, 15955093, 25360671) -

not specified

Benign:1

May 26, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aicardi-Goutieres syndrome 6

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.96

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.21

T;.;T;.;.;.;.;.;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.62

.;.;T;.;.;.;.;.;T;T;T

MetaRNN

Benign

0.0026

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.060

N;.;N;.;.;.;.;.;.;N;.

PhyloP100

-0.77

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.11

N;.;.;.;N;.;.;.;.;.;.

REVEL

Benign

0.0030

Sift

Benign

0.18

T;.;.;.;T;.;.;.;.;.;.

Sift4G

Benign

0.18

T;.;.;.;T;.;.;.;.;.;.

Polyphen

0.0010

B;.;B;.;.;.;.;.;.;B;.

Vest4

0.083

MVP

0.093

MPC

0.30

ClinPred

0.00013

GERP RS

-6.4

Varity_R

0.032

gMVP

0.21

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over