1-154602065-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3PP5BP4

The NM_001111.5(ADAR):c.577C>G(p.Pro193Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,614,176 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002041618: A publication also reported experimental evidence evaluating an impact on protein function, and demonstrated a partial loss of function for the variant protein (Mannion_2014)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P193L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 5 hom. )

Consequence

ADAR
NM_001111.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:25U:3O:2

Conservation

PhyloP100: 8.43

Publications

85 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 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

ADAR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PS3

PS3 evidence extracted from ClinVar submissions: SCV002041618: A publication also reported experimental evidence evaluating an impact on protein function, and demonstrated a partial loss of function for the variant protein (Mannion_2014).; SCV002768143: "In addition, functional studies show that this variant causes reductions in RNA editing efficiency, but only in compound heterozygote with another pathogenic variant (Mannion, N. M. et al. (2014))."; SCV000321382: knock-in mouse model for this variant supports that it could be a hypomorph variant (PMID: 34343497); SCV002064425: Functional studies in HEK293 cells transfected with the p.Pro193Ala variant exhibit a significant decrease in RNA-editing enzyme activity (Mannion et al., 2014).; SCV000742076: "In one study, functional analysis in HEK293 cells demonstrated that the p.P193A alteration results in significantly decreased RNA-editing activity compared to wildtype (Mannion, 2014)"; SCV000914349: Expression analysis of p.Pro193Ala in HEK293 cells showed a significant reduction in RNA-editing enzyme activity (Mannion et al. 2014).; SCV004105363: This variant has been reported in the compound heterozygous state in multiple families with Aicardi-Goutières syndrome and is predicted to disrupt DNA binding (Rice et al. 2012. PubMed ID: 23001123; Livingston et al. 2015. PubMed ID: 24262145; Piekutowska-Abramczuk et al. 2016. PubMed ID: 28139822).

PP5

Variant 1-154602065-G-C is Pathogenic according to our data. Variant chr1-154602065-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126395.

BP4

Computational evidence support a benign effect (MetaRNN=0.037495464). . Strength limited to SUPPORTING due to the PP5.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAR	NM_001111.5	MANE Select	c.577C>G	p.Pro193Ala	missense	Exon 2 of 15	NP_001102.3	P55265-1
ADAR	NM_001365045.1		c.604C>G	p.Pro202Ala	missense	Exon 2 of 15	NP_001351974.1
ADAR	NM_015840.4		c.577C>G	p.Pro193Ala	missense	Exon 2 of 15	NP_056655.3	P55265-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAR	ENST00000368474.9	TSL:1 MANE Select	c.577C>G	p.Pro193Ala	missense	Exon 2 of 15	ENSP00000357459.4	P55265-1
ADAR	ENST00000368471.8	TSL:1	c.-309C>G		5_prime_UTR	Exon 2 of 15	ENSP00000357456.3	P55265-5
ADAR	ENST00000649724.2		c.607C>G	p.Pro203Ala	missense	Exon 2 of 15	ENSP00000497932.2	A0AAG2TPY2

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

350

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00357

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00221

AC:

555

AN:

251460

AF XY:

0.00229

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00338

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00325

AC:

4748

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

2284

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33480

American (AMR)

AF:

0.00304

AC:

136

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000951

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000786

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00388

AC:

4310

AN:

1112000

Other (OTH)

AF:

0.00253

AC:

153

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

344

689

1033

1378

1722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<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:

0.00230

AC:

351

AN:

152316

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

156

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000842

AC:

AN:

41566

American (AMR)

AF:

0.00366

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00357

AC:

243

AN:

68016

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00183

Hom.:

Bravo

AF:

0.00251

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00214

AC:

260

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00349

EpiControl

AF:

0.00391

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aicardi-Goutieres syndrome 6 (11)

not provided (7)

Symmetrical dyschromatosis of extremities (3)

Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 (4)

ADAR-related disorder (2)

ADAR-related type 1 interferonopathy (1)

Aicardi Goutieres syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.037

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.9

PhyloP100

8.4

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.57

MVP

0.85

MPC

0.87

ClinPred

0.041

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.58

Mutation Taster

=72/28

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over