rs398122893

Variant names:

• chr1-154589817-C-T
• rs398122893
• NM_001111.5:c.2608G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_001111.5(ADAR):​c.2608G>A​(p.Ala870Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A870A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 1-154589817-C-T is Pathogenic according to our data. Variant chr1-154589817-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39456.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-154589817-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAR	NM_001111.5	c.2608G>A	p.Ala870Thr	missense_variant	Exon 8 of 15	ENST00000368474.9	NP_001102.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAR	ENST00000368474.9	c.2608G>A	p.Ala870Thr	missense_variant	Exon 8 of 15	1	NM_001111.5	ENSP00000357459.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Aicardi-Goutieres syndrome 6 Pathogenic:2

Jun 27, 2013

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;.;D;.;.;.;.;.;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.7	L;.;L;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.6	D;.;.;.;D;.;.;.;.;.
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;.;.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;.;.;.;D;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;D
Vest4		0.92
MutPred		0.39		Loss of stability (P = 0.1127);.;Loss of stability (P = 0.1127);.;.;.;.;.;.;.;
MVP		0.86
MPC		2.0
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.78
gMVP		0.93

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

Other links and lift over

dbSNP: rs398122893; hg19: chr1-154562293;