rs753679297
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_006397.3(RNASEH2A):c.557G>A(p.Arg186Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R186W) has been classified as Pathogenic.
Frequency
Consequence
NM_006397.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RNASEH2A | NM_006397.3 | c.557G>A | p.Arg186Gln | missense_variant | 6/8 | ENST00000221486.6 | NP_006388.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RNASEH2A | ENST00000221486.6 | c.557G>A | p.Arg186Gln | missense_variant | 6/8 | 1 | NM_006397.3 | ENSP00000221486.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727244
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Aicardi-Goutieres syndrome 4 Pathogenic:7
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 186 of the RNASEH2A protein (p.Arg186Gln). This variant is present in population databases (rs753679297, gnomAD 0.0009%). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 24300241, 29239743). ClinVar contains an entry for this variant (Variation ID: 445579). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RNASEH2A protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Nov 04, 2022 | PM2, PM5, PP3, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 12, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PM3(strong),PM2,PP3,PP1,PM5 - |
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 04, 2017 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 07, 2022 | Observed with a second RNASEH2A variant, phase unknown, in an individual with Aicardi-Goutieres syndrome (Abe et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29239743, 34374989, 31130284, 24300241, 36065636) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2022 | The c.557G>A (p.R186Q) alteration is located in exon 6 (coding exon 6) of the RNASEH2A gene. This alteration results from a G to A substitution at nucleotide position 557, causing the arginine (R) at amino acid position 186 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/251488) total alleles studied. This variant has been reported in the homozygous and compound heterozygous state in patients with features of Aicardi-Goutières syndrome (Abe, 2014; Al Mutairi, 2018; Monies, 2017; Monies, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
RNASEH2A-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 30, 2024 | The RNASEH2A c.557G>A variant is predicted to result in the amino acid substitution p.Arg186Gln. This variant has been reported many times in both the homozygous and compound heterozygous states in individuals with Aicardi-Goutieres syndrome (see for examples, Abe et al. 2014. PubMed ID: 24300241; Al Mutairi et al. 2017. PubMed ID: 29239743; Table S1, Monies et al. 2019. PubMed ID: 31130284; Saleh et al. 2021. PubMed ID: 34374989). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/445579/). Given the evidence, we interpret this variant as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at