chr1-154583257-A-T

Variant names:

• chr1-154583257-A-T
• rs9616
• NM_001111.5:c.*1549T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001111.5(ADAR):​c.*1549T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,268 control chromosomes in the GnomAD database, including 4,443 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4442 hom., cov: 32)
  • Exomes 𝑓: 0.21 (1 hom.)
• Consequence: ADAR NM_001111.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.300
• Publications: 29 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAR	NM_001111.5	c.*1549T>A		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.*1549T>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_001111.5	ENSP00000357459.4

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32913 AN: 152094 Hom.: 4440 Cov.: 32

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.214 AC: 12 AN: 56 Hom.: 1 Cov.: 0 AF XY: 0.225 AC XY: 9 AN XY: 40

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.100 AC: 3 AN: 30

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.375 AC: 9 AN: 24

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.216 AC: 32913 AN: 152212 Hom.: 4442 Cov.: 32 AF XY: 0.215 AC XY: 15968 AN XY: 74408

African (AFR) AF: 0.0558 AC: 2319 AN: 41558

American (AMR) AF: 0.317 AC: 4848 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 995 AN: 3470

East Asian (EAS) AF: 0.334 AC: 1722 AN: 5156

South Asian (SAS) AF: 0.167 AC: 806 AN: 4826

European-Finnish (FIN) AF: 0.197 AC: 2083 AN: 10584

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.284 AC: 19288 AN: 68006

Other (OTH) AF: 0.229 AC: 483 AN: 2106

Alfa AF: 0.237 Hom.: 620

Bravo AF: 0.223

Asia WGS AF: 0.190 AC: 665 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	-0.85
CADD	Benign	2.3
DANN	Benign	0.77
PhyloP100		-0.30
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: rs9616; hg19: chr1-154555733;