NM_001111.5:c.*619C>T

Variant names:

• chr1-154584187-G-A
• rs1127311
• NM_001111.5:c.*619C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001111.5(ADAR):​c.*619C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 152,404 control chromosomes in the GnomAD database, including 14,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14253 hom., cov: 33)
  • Exomes 𝑓: 0.44 (36 hom.)
• Consequence: ADAR NM_001111.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.27
• Publications: 26 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

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• dyschromatosis symmetrica hereditaria

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Aicardi-Goutieres syndrome 6

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-154584187-G-A is Benign according to our data. Variant chr1-154584187-G-A is described in ClinVar as Benign. ClinVar VariationId is 292740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAR	NM_001111.5	c.*619C>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000368474.9	NP_001102.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAR	ENST00000368474.9	c.*619C>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_001111.5	ENSP00000357459.4

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63681 AN: 151982 Hom.: 14252 Cov.: 33

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.419

GnomAD4 exome AF: 0.444 AC: 135 AN: 304 Hom.: 36 Cov.: 0 AF XY: 0.463 AC XY: 76 AN XY: 164

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 0.375 AC: 12 AN: 32

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.167 AC: 3 AN: 18

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.474 AC: 110 AN: 232

Other (OTH) AF: 0.500 AC: 8 AN: 16

GnomAD4 genome AF: 0.419 AC: 63681 AN: 152100 Hom.: 14253 Cov.: 33 AF XY: 0.420 AC XY: 31218 AN XY: 74362

African (AFR) AF: 0.257 AC: 10659 AN: 41510

American (AMR) AF: 0.477 AC: 7292 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1735 AN: 3466

East Asian (EAS) AF: 0.553 AC: 2862 AN: 5174

South Asian (SAS) AF: 0.412 AC: 1988 AN: 4828

European-Finnish (FIN) AF: 0.439 AC: 4636 AN: 10550

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.485 AC: 32980 AN: 67972

Other (OTH) AF: 0.415 AC: 874 AN: 2108

Alfa AF: 0.466 Hom.: 21679

Bravo AF: 0.418

Asia WGS AF: 0.436 AC: 1519 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Symmetrical dyschromatosis of extremities Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.29
DANN	Benign	0.56
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs1127311; hg19: chr1-154556663;