rs28936680

chr1-154588668-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001111.5(ADAR):c.2768T>C(p.Leu923Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L923L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.73

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ADAR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 1-154588668-A-G is Pathogenic according to our data. Variant chr1-154588668-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 14818.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAR	NM_001111.5	c.2768T>C	p.Leu923Pro	missense_variant	10/15	ENST00000368474.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAR	ENST00000368474.9	c.2768T>C	p.Leu923Pro	missense_variant	10/15	1	NM_001111.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Symmetrical dyschromatosis of extremities Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;H;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.1	D;.;.;.;D;.;.;.;.;.
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;.;.;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.;D;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;D
Vest4		0.97
MutPred		0.98		Loss of stability (P = 0.0243);.;Loss of stability (P = 0.0243);.;.;.;.;.;.;.;
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.99

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: rs28936680; hg19: chr1-154561144;