1-154601491-T-C

Position:

chr1-154601491-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

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. 13/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.324

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PM1

In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) (size 0) in uniprot entity DSRAD_HUMAN

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADAR. . Gene score misZ 2.2714 (greater than the threshold 3.09). Trascript score misZ 3.4067 (greater than threshold 3.09). GenCC has associacion of gene with dyschromatosis symmetrica hereditaria, Aicardi-Goutieres syndrome, Aicardi-Goutieres syndrome 6, Leigh syndrome, familial infantile bilateral striatal necrosis.

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 id is 195112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154601491-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAR	NM_001111.5 linkuse as main transcript	c.1151A>G	p.Lys384Arg	missense_variant	2/15	ENST00000368474.9	NP_001102.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAR	ENST00000368474.9 linkuse as main transcript	c.1151A>G	p.Lys384Arg	missense_variant	2/15	1	NM_001111.5	ENSP00000357459	P3	P55265-1

Frequencies

GnomAD3 genomes

AF:

0.626

AC:

95137

AN:

152016

Hom.:

31043

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.703

AC:

176710

AN:

251442

Hom.:

63170

AF XY:

0.705

AC XY:

95877

AN XY:

135900

show subpopulations

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 SAS exome

AF:

0.754

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.:

AF XY:

0.702

AC XY:

510715

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.417

Gnomad4 AMR exome

AF:

0.806

Gnomad4 ASJ exome

AF:

0.707

Gnomad4 EAS exome

AF:

0.730

Gnomad4 SAS exome

AF:

0.760

Gnomad4 FIN exome

AF:

0.664

Gnomad4 NFE exome

AF:

0.699

Gnomad4 OTH exome

AF:

0.680

GnomAD4 genome

AF:

0.626

AC:

95169

AN:

152134

Hom.:

31054

Cov.:

AF XY:

0.630

AC XY:

46865

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.420

Gnomad4 AMR

AF:

0.730

Gnomad4 ASJ

AF:

0.723

Gnomad4 EAS

AF:

0.706

Gnomad4 SAS

AF:

0.768

Gnomad4 FIN

AF:

0.652

Gnomad4 NFE

AF:

0.701

Gnomad4 OTH

AF:

0.638

Alfa

AF:

0.690

Hom.:

95117

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

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 90% of patients studied by a panel of primary immunodeficiencies. Number of patients: 86. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	This variant is associated with the following publications: (PMID: 25098560, 31423758) -

Symmetrical dyschromatosis of extremities

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Aicardi-Goutieres syndrome 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.18

DANN

Benign

0.94

DEOGEN2

Benign

0.28

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.42

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

MetaRNN

Benign

0.0000012

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

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.0

M;.;M;.;.;.;.;.;.;M;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.070

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

REVEL

Benign

0.012

Sift

Benign

0.38

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

Sift4G

Benign

0.65

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

Polyphen

0.0

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

Vest4

0.011

MPC

0.20

ClinPred

0.0030

GERP RS

-0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.017

gMVP

0.072

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over