rs34154757

Variant names:

• chr1-154601639-T-A
• rs34154757
• NM_001111.5:c.1003A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-154601639-T-A
• chr1-154601639-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001111.5(ADAR):​c.1003A>T​(p.Ile335Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,613,908 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.204
• Publications: 1 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), PanelApp Australia, Ambry Genetics
• dyschromatosis symmetrica hereditaria

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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 (MetaRNN=0.006111294).
• BP6: Variant 1-154601639-T-A is Benign according to our data. Variant chr1-154601639-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00229 (349/152350) while in subpopulation AFR AF = 0.00734 (305/41578). AF 95% confidence interval is 0.00666. There are 1 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.1003A>T	p.Ile335Phe	missense	Exon 2 of 15	NP_001102.3	P55265-1
	ADAR	NM_001365045.1		c.1030A>T	p.Ile344Phe	missense	Exon 2 of 15	NP_001351974.1
	ADAR	NM_015840.4		c.1003A>T	p.Ile335Phe	missense	Exon 2 of 15	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.1003A>T	p.Ile335Phe	missense	Exon 2 of 15	ENSP00000357459.4	P55265-1
	ADAR	ENST00000368471.8	TSL:1	c.118A>T	p.Ile40Phe	missense	Exon 2 of 15	ENSP00000357456.3	P55265-5
	ADAR	ENST00000649724.2		c.1033A>T	p.Ile345Phe	missense	Exon 2 of 15	ENSP00000497932.2	A0AAG2TPY2

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 349 AN: 152232 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.000797 AC: 200 AN: 251084 AF XY: 0.000604

Gnomad AFR exome AF: 0.00825

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000268 AC: 391 AN: 1461558 Hom.: 2 Cov.: 89 AF XY: 0.000248 AC XY: 180 AN XY: 727102

African (AFR) AF: 0.00657 AC: 220 AN: 33480

American (AMR) AF: 0.00145 AC: 65 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1112010

Other (OTH) AF: 0.000861 AC: 52 AN: 60392

GnomAD4 genome AF: 0.00229 AC: 349 AN: 152350 Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74510

African (AFR) AF: 0.00734 AC: 305 AN: 41578

American (AMR) AF: 0.00183 AC: 28 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.000872 Hom.: 0

Bravo AF: 0.00260

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Aicardi-Goutieres syndrome 6 (1)
-	-	1	Symmetrical dyschromatosis of extremities (1)
-	-	1	Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L
PhyloP100		0.20
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.086
Sift	Benign	0.46	T
Sift4G	Benign	0.69	T
Polyphen		0.97	D
Vest4		0.084
MVP		0.71
MPC		0.39
ClinPred		0.0015	T
GERP RS		-0.60
Varity_R		0.083
gMVP		0.11
Mutation Taster		=77/23	polymorphism

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: rs34154757; hg19: chr1-154574115;