chr1-154602065-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate

The NM_001111.5(ADAR):​c.577C>A​(p.Pro193Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P193A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADAR
NM_001111.5 missense

Scores

8
9
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.43
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-154602065-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126395.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=12, Likely_pathogenic=7, not_provided=2}.
PP2
Missense variant in the ADAR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 30 curated benign missense variants. Gene score misZ: 2.2714 (below the threshold of 3.09). Trascript score misZ: 3.4067 (above the threshold of 3.09). GenCC associations: The gene is linked to dyschromatosis symmetrica hereditaria, Aicardi-Goutieres syndrome, Aicardi-Goutieres syndrome 6, Leigh syndrome, familial infantile bilateral striatal necrosis.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADARNM_001111.5 linkc.577C>A p.Pro193Thr missense_variant Exon 2 of 15 ENST00000368474.9 NP_001102.3 P55265-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADARENST00000368474.9 linkc.577C>A p.Pro193Thr missense_variant Exon 2 of 15 1 NM_001111.5 ENSP00000357459.4 P55265-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251460
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135900
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461860
Hom.:
0
Cov.:
89
AF XY:
0.00000138
AC XY:
1
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;D;.
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.88
.;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.89
D;D;D
MetaSVM
Uncertain
0.18
D
MutationAssessor
Uncertain
2.8
M;M;M
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-3.0
D;.;.
REVEL
Pathogenic
0.74
Sift
Pathogenic
0.0
D;.;.
Sift4G
Pathogenic
0.0
D;.;.
Polyphen
1.0
D;D;D
Vest4
0.75
MutPred
0.68
Loss of catalytic residue at P192 (P = 0.011);Loss of catalytic residue at P192 (P = 0.011);Loss of catalytic residue at P192 (P = 0.011);
MVP
0.77
MPC
0.94
ClinPred
0.99
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.67

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.

Other links and lift over

dbSNP: rs145588689; hg19: chr1-154574541; API