rs2229857

Positions:

• chr1-154601491-T-A
• chr1-154601491-T-C
• chr1-154601491-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001111.5(ADAR):​c.1151A>T​(p.Lys384Ile) 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. 14/21 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 3 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 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=0.08387461).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAR	NM_001111.5	c.1151A>T	p.Lys384Ile	missense_variant	2/15	ENST00000368474.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAR	ENST00000368474.9	c.1151A>T	p.Lys384Ile	missense_variant	2/15	1	NM_001111.5	P3

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	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.91
DANN	Benign	0.97
DEOGEN2	Uncertain	0.44	T;.;T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.66	.;.;T;.;.;.;.;.;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.084	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	M;.;M;.;.;.;.;.;.;M;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.95	N;.;.;.;N;.;.;.;.;.;.
REVEL	Benign	0.030
Sift	Benign	0.072	T;.;.;.;T;.;.;.;.;.;.
Sift4G	Benign	0.12	T;.;.;.;T;.;.;.;.;.;.
Polyphen		0.26	B;.;B;.;.;.;.;.;.;B;.
Vest4		0.17
MutPred		0.35		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		0.23
MPC		0.43
ClinPred		0.085	T
GERP RS		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.070
gMVP		0.16

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;