rs9427094

Variant names:

• chr1-154585209-C-T
• rs9427094
• NM_001111.5:c.3443+8G>A

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.3443+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,613,746 control chromosomes in the GnomAD database, including 182,154 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13975 hom., cov: 31)
  • Exomes 𝑓: 0.48 (168179 hom.)
• Consequence: ADAR NM_001111.5 splice_region, intron
• Scores: Splicing: ADA: 0.0004036
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 1.78
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-154585209-C-T is Benign according to our data. Variant chr1-154585209-C-T is described in ClinVar as Benign. ClinVar VariationId is 257475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111.5. 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.3443+8G>A		splice_region intron	N/A	NP_001102.3	P55265-1
	ADAR	NM_001365045.1		c.3470+8G>A		splice_region intron	N/A	NP_001351974.1
	ADAR	NM_015840.4		c.3365+8G>A		splice_region intron	N/A	NP_056655.3	P55265-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAR	ENST00000368474.9	TSL:1 MANE Select	c.3443+8G>A		splice_region intron	N/A	ENSP00000357459.4	P55265-1
	ADAR	ENST00000368471.8	TSL:1	c.2558+8G>A		splice_region intron	N/A	ENSP00000357456.3	P55265-5
	ADAR	ENST00000649724.2		c.3473+8G>A		splice_region intron	N/A	ENSP00000497932.2	A0AAG2TPY2

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62772 AN: 151788 Hom.: 13973 Cov.: 31

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.416

GnomAD2 exomes AF: 0.466 AC: 117123 AN: 251442 AF XY: 0.464

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.535

Gnomad FIN exome AF: 0.440

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.477 AC: 697104 AN: 1461840 Hom.: 168179 Cov.: 60 AF XY: 0.476 AC XY: 346518 AN XY: 727222

African (AFR) AF: 0.237 AC: 7939 AN: 33480

American (AMR) AF: 0.517 AC: 23108 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 12757 AN: 26136

East Asian (EAS) AF: 0.560 AC: 22243 AN: 39698

South Asian (SAS) AF: 0.415 AC: 35759 AN: 86248

European-Finnish (FIN) AF: 0.451 AC: 24090 AN: 53416

Middle Eastern (MID) AF: 0.424 AC: 2447 AN: 5768

European-Non Finnish (NFE) AF: 0.487 AC: 541062 AN: 1111978

Other (OTH) AF: 0.459 AC: 27699 AN: 60392

GnomAD4 genome AF: 0.413 AC: 62776 AN: 151906 Hom.: 13975 Cov.: 31 AF XY: 0.414 AC XY: 30773 AN XY: 74274

African (AFR) AF: 0.243 AC: 10065 AN: 41422

American (AMR) AF: 0.476 AC: 7263 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 1728 AN: 3470

East Asian (EAS) AF: 0.538 AC: 2769 AN: 5148

South Asian (SAS) AF: 0.411 AC: 1973 AN: 4804

European-Finnish (FIN) AF: 0.438 AC: 4620 AN: 10536

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32835 AN: 67946

Other (OTH) AF: 0.411 AC: 866 AN: 2106

Alfa AF: 0.449 Hom.: 7401

Bravo AF: 0.412

Asia WGS AF: 0.433 AC: 1506 AN: 3478

EpiCase AF: 0.480

EpiControl AF: 0.478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Symmetrical dyschromatosis of extremities (2)
-	-	1	Aicardi-Goutieres syndrome 6 (1)
-	-	1	not provided (2)
-	-	1	Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.3
DANN	Benign	0.51
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00040
dbscSNV1_RF	Benign	0.010
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: rs9427094; hg19: chr1-154557685; COSMIC: COSV52718582; COSMIC: COSV52718582;