rs398122822

Positions:

• chr1-154588125-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001111.5(ADAR):​c.3019G>A​(p.Gly1007Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAR NM_001111.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 7.13

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001111.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ADAR
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-154588125-C-T is Pathogenic according to our data. Variant chr1-154588125-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154588125-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAR	NM_001111.5	c.3019G>A	p.Gly1007Arg	missense_variant, splice_region_variant	11/15	ENST00000368474.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAR	ENST00000368474.9	c.3019G>A	p.Gly1007Arg	missense_variant, splice_region_variant	11/15	1	NM_001111.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461336 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726956

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.00210 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 6 Pathogenic:11 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 30, 2020	This ADAR variant is absent from a large population dataset and has an entry in ClinVar. It has been reported in at least eleven individuals from nine families with autosomal dominant Aicardi-Goutieres syndrome. In four families, the c.3019G>A variant occurred de novo. Independent functional studies have shown that the p.Gly1007Arg substitution inhibits the RNA editing activity of ADAR1, presumably through steric hindrance at the base-flipping step of the deaminase reaction. We consider this variant to be pathogenic. -
Likely pathogenic, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 27, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2024	heterozygous -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 17, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Mar 01, 2024	The NM_001111.5: c.3019G>A variant is located in exon 11 of the ADAR gene. This variant involves a change at the protein level from Glycine to Arginine at position 1007 (p.(Gly1007Arg)). This position is highly conserved and corresponds to a well-established domain of the protein. This variant has a null frequency in population databases and, in turn, has numerous reports in ClinVar, where it is classified as likely pathogenic/pathogenic (ClinVarID: 39458). In addition, more than 4 cases have been reported in which the variant was found 'de novo' (PMID: 23001123, 33307271). On the other hand, bioinformatic tools predict that the variant would be deleterious, which agrees with what has been demonstrated through functional studies (PMID: 25243380, 26372505). It is important to highlight that, although patients with the AGS phenotype associated with an autosomal recessive inheritance pattern have been described, this particular variant behaves as dominant-negative, so affected patients are heterozygous for said variant. (PS3supporting, PM1supporting, PM2moderate, PM6strong, PP3moderate) -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wangler Lab, Baylor College of Medicine	-	This ADAR variant at c.3019G>A (p.G1007R) was seen on exome through the Texome project (R01HG011795). This variant has been described as a de novo variant in the heterozygous state in individuals with autosomal dominant Aicardi-Goutières syndrome (PMID: 23001123, 33307271) and in individuals with dyschromatosis symmetrica hereditaria with additional features including dystonia, mental deterioration and brain MRI abnormalities (PMID: 16817193, 19017046). In addition, this heterozygous variant has been described in two individuals with tremors, spasticity/dystonia, abnormal MRI findings and progressive motor deterioration (PMID: 24262145, 29691679) and two internal cases with a similar phenotype. This variant is absent from gnomAD (PM2). Functional studies suggest this variant showed a significant effect on editing function of the protein, with levels of editing equivalent to those seen with inactive protein (PMID: 23001123) (PS3). This heterozygous variant shows RNA editing deficiency similar to Aicardi-Goutières associated variants and more severely affected when compared to dyschromatosis symmetrica hereditaria associated variants (PMID: 26802932).This variant lies at the last nucleotide of exon 11 (of 15) for the reported transcript. This variant is predicted to be deleterious(CADD: 34.000, SpliceAI: 0.190) (PP3). The evolutionary conservation of this residue is high. Variant is located in the adenosinede aminase/editase domain (PMID: 23001123). We classify this variant as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.G1007R in ADAR (NM_001111.5) has been previously reported in multiple individuals with dominant Aicardi Goutieres syndrome (Kondo T et al,2008). Functional analysis revealed a damagig effect (Fisher AJ et al,2017). The variant has been submitted to ClinVar as Pathogenic. The p.G1007R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G1007R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.3019 in ADAR is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	Jun 28, 2022	Criteria Codes: PS3 PS4_Mod PM2 PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 13, 2023	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change affects ADAR function (PMID: 26802932, 29775506). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 39458). This missense change has been observed in individual(s) with clinical features of autosomal dominant dyschromatosis symmetrica hereditaria and/or autosomal dominant Aicardi Goutieres syndrome (PMID: 15955093, 16817193, 19017046, 23001123, 24262145, 25243380, 28561207, 29691679, 32801363, 33307271). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1007 of the ADAR protein (p.Gly1007Arg). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ADAR: PS2, PM2, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2022	Reported in published literature in multiple affected individuals from a few unrelated families with dyschromatosis symmetrica hereditaria and neurodegeneration with dystonia and intracranial calcification. Also present in multiple unaffected relatives in these families, suggesting G1007R may exhibit incomplete penetrance (Suzuki et al., 2005; Kondo et al., 2008); Published functional studies suggest that G1007R may confer a dominant-negative effect by binding more tightly to RNA and acting as competitive inhibitor to the wild-type protein (Rice et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29775506, 24262145, 25243380, 19017046, 16817193, 27959697, 15955093, 23001123, 29691679, 31737037, 34426522, 32801363, 33307271, 27535533) -

Symmetrical dyschromatosis of extremities Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	May 14, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.8	M;.;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.3	D;.;.;.;D;.;.;.;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;.;.;.;D;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;D
Vest4		0.94
MutPred		0.69		Gain of solvent accessibility (P = 0.0014);.;Gain of solvent accessibility (P = 0.0014);.;.;.;.;.;.;.;
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398122822; hg19: chr1-154560601;