rs921496664

Variant names:

• chr1-154602167-G-C
• rs921496664
• NM_001111.5:c.475C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001111.5(ADAR):​c.475C>G​(p.His159Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,884 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0540
• 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 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12139392).

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.475C>G	p.His159Asp	missense	Exon 2 of 15	NP_001102.3	P55265-1
	ADAR	NM_001365045.1		c.502C>G	p.His168Asp	missense	Exon 2 of 15	NP_001351974.1
	ADAR	NM_015840.4		c.475C>G	p.His159Asp	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.475C>G	p.His159Asp	missense	Exon 2 of 15	ENSP00000357459.4	P55265-1
	ADAR	ENST00000368471.8	TSL:1	c.-411C>G		5_prime_UTR	Exon 2 of 15	ENSP00000357456.3	P55265-5
	ADAR	ENST00000649724.2		c.505C>G	p.His169Asp	missense	Exon 2 of 15	ENSP00000497932.2	A0AAG2TPY2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461884 Hom.: 0 Cov.: 89 AF XY: 0.0000179 AC XY: 13 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 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: 53418

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

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (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	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.054
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.074
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.020	D
Polyphen		0.12	B
Vest4		0.28
MutPred		0.57		Gain of ubiquitination at K164 (P = 0.0398)
MVP		0.61
MPC		0.35
ClinPred		0.15	T
GERP RS		-0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.69
gMVP		0.23
Mutation Taster		=81/19	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: rs921496664; hg19: chr1-154574643;