chr1-154589456-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001111.5(ADAR):c.2675G>A(p.Arg892His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R892R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ADAR
NM_001111.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 5.48

Publications

15 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAR	NM_001111.5 link	c.2675G>A	p.Arg892His	missense_variant	Exon 9 of 15	ENST00000368474.9	NP_001102.3	P55265-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAR	ENST00000368474.9 link	c.2675G>A	p.Arg892His	missense_variant	Exon 9 of 15	1	NM_001111.5	ENSP00000357459.4		P55265-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

251106

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459864

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726418

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110272

Other (OTH)

AF:

0.00

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 6

Pathogenic:2

Nov 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 27, 2013

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Uncertain:1

Oct 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 892 of the ADAR protein (p.Arg892His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Aicardi Goutieres syndrome (PMID: 23001123). ClinVar contains an entry for this variant (Variation ID: 39455). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADAR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;.;D;.;.;.;.;.;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.97

.;.;D;.;.;.;.;.;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

2.9

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

PhyloP100

5.5

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.9

D;.;.;.;D;.;.;.;.;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0020

D;.;.;.;D;.;.;.;.;.

Sift4G

Uncertain

0.0030

D;.;.;.;D;.;.;.;.;.

Polyphen

1.0

D;.;D;.;.;.;.;.;.;D

Vest4

0.87

MutPred

0.80

Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);.;.;.;.;.;.;.;

MVP

0.98

MPC

2.2

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.85

gMVP

0.82

Mutation Taster

=9/91

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over