1-154602344-T-A

Variant names:

• chr1-154602344-T-A
• rs1466731
• ENST00000368471.8:c.-588A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001025107.3(ADAR):​c.-588A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,562 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ADAR NM_001025107.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 30 publications found

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]

ADAR Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 6

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyschromatosis symmetrica hereditaria

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• ADAR-related type 1 interferonopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial infantile bilateral striatal necrosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.597

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025107.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAR	NM_001111.5	MANE Select	c.298A>T	p.Arg100*	stop_gained	Exon 2 of 15	NP_001102.3	P55265-1
	ADAR	NM_001025107.3		c.-588A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	NP_001020278.1	P55265-5
	ADAR	NM_001193495.2		c.-588A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	NP_001180424.1	P55265-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAR	ENST00000368471.8	TSL:1	c.-588A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	ENSP00000357456.3	P55265-5
	ADAR	ENST00000368474.9	TSL:1 MANE Select	c.298A>T	p.Arg100*	stop_gained	Exon 2 of 15	ENSP00000357459.4	P55265-1
	ADAR	ENST00000368471.8	TSL:1	c.-588A>T		5_prime_UTR	Exon 2 of 15	ENSP00000357456.3	P55265-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457562 Hom.: 0 Cov.: 81 AF XY: 0.00 AC XY: 0 AN XY: 725052

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25660

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 85614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109698

Other (OTH) AF: 0.00 AC: 0 AN: 60196

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.61
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
PhyloP100		-1.2
Vest4		0.53
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=13/187	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs1466731; hg19: chr1-154574820;