1-154601491-T-G

Variant names:

• chr1-154601491-T-G
• rs2229857
• NM_001111.5:c.1151A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM2 PP2 BP4_Strong

The NM_001111.5(ADAR):​c.1151A>C​(p.Lys384Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. K384R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.324

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 1 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
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.058048993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAR	NM_001111.5	c.1151A>C	p.Lys384Thr	missense_variant	Exon 2 of 15	ENST00000368474.9	NP_001102.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAR	ENST00000368474.9	c.1151A>C	p.Lys384Thr	missense_variant	Exon 2 of 15	1	NM_001111.5	ENSP00000357459.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 78

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.16
DANN	Benign	0.92
DEOGEN2	Benign	0.25	T;.;T;.;.;.;.;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.53	.;.;T;.;.;.;.;.;T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.058	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L;.;L;.;.;.;.;.;.;L;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.16	N;.;.;.;N;.;.;.;.;.;.
REVEL	Benign	0.0090
Sift	Benign	0.52	T;.;.;.;T;.;.;.;.;.;.
Sift4G	Benign	0.45	T;.;.;.;T;.;.;.;.;.;.
Polyphen		0.0010	B;.;B;.;.;.;.;.;.;B;.
Vest4		0.066
MutPred		0.29		Loss of ubiquitination at K384 (P = 0.0051);.;Loss of ubiquitination at K384 (P = 0.0051);.;.;.;.;.;.;Loss of ubiquitination at K384 (P = 0.0051);.;
MVP		0.18
MPC		0.29
ClinPred		0.076	T
GERP RS		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.030
gMVP		0.12

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: rs2229857; hg19: chr1-154573967;