chr1-154601539-T-C

Variant names:

• chr1-154601539-T-C
• rs1553213121
• NM_001111.5:c.1103A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001111.5(ADAR):​c.1103A>G​(p.Asn368Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N368I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.392
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036102116).

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.1103A>G	p.Asn368Ser	missense	Exon 2 of 15	NP_001102.3	P55265-1
	ADAR	NM_001365045.1		c.1130A>G	p.Asn377Ser	missense	Exon 2 of 15	NP_001351974.1
	ADAR	NM_015840.4		c.1103A>G	p.Asn368Ser	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.1103A>G	p.Asn368Ser	missense	Exon 2 of 15	ENSP00000357459.4	P55265-1
	ADAR	ENST00000368471.8	TSL:1	c.218A>G	p.Asn73Ser	missense	Exon 2 of 15	ENSP00000357456.3	P55265-5
	ADAR	ENST00000649724.2		c.1133A>G	p.Asn378Ser	missense	Exon 2 of 15	ENSP00000497932.2	A0AAG2TPY2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 89

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.1
DANN	Benign	0.37
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.57	N
PhyloP100		0.39
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.043
Sift	Benign	0.56	T
Sift4G	Benign	0.58	T
Polyphen		0.0020	B
Vest4		0.023
MutPred		0.22		Gain of glycosylation at N368 (P = 0.034)
MVP		0.29
MPC		0.19
ClinPred		0.022	T
GERP RS		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.086
Mutation Taster		=98/2	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: rs1553213121; hg19: chr1-154574015;