1-154601639-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001111.5(ADAR):​c.1003A>G​(p.Ile335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I335F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.204
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09299433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAR	NM_001111.5	c.1003A>G	p.Ile335Val	missense_variant	Exon 2 of 15	ENST00000368474.9	NP_001102.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAR	ENST00000368474.9	c.1003A>G	p.Ile335Val	missense_variant	Exon 2 of 15	1	NM_001111.5	ENSP00000357459.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461558 Hom.: 0 Cov.: 89 AF XY: 0.00000138 AC XY: 1 AN XY: 727102

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.8
DANN	Benign	0.91
DEOGEN2	Benign	0.29	T;.;T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.62	.;.;T;.;.;.;.;.;T;T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.093	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;L;.;.;.;.;.;.;L;.
PhyloP100		0.20
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.16	N;.;.;.;N;.;.;.;.;.;.
REVEL	Benign	0.039
Sift	Benign	0.54	T;.;.;.;T;.;.;.;.;.;.
Sift4G	Benign	0.63	T;.;.;.;T;.;.;.;.;.;.
Polyphen		0.44	B;.;B;.;.;.;.;.;.;B;.
Vest4		0.037
MutPred		0.52		Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);.;.;.;.;.;.;Loss of helix (P = 0.079);.;
MVP		0.45
MPC		0.21
ClinPred		0.081	T
GERP RS		-0.60
Varity_R		0.041
gMVP		0.076
Mutation Taster		=73/27	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;