GeneBe

RNASEH2A

protein-coding

ribonuclease H2 subunit A

Gene summary

The protein encoded by this gene is a component of the heterotrimeric type II ribonuclease H enzyme (RNAseH2). RNAseH2 is the major source of ribonuclease H activity in mammalian cells and endonucleolytically cleaves ribonucleotides. It is predicted to remove Okazaki fragment RNA primers during lagging strand DNA synthesis and to excise single ribonucleotides from DNA-DNA duplexes. Mutations in this gene cause Aicardi-Goutieres Syndrome (AGS), a an autosomal recessive neurological disorder characterized by progressive microcephaly and psychomotor retardation, intracranial calcifications, elevated levels of interferon-alpha and white blood cells in the cerebrospinal fluid.[provided by RefSeq, Aug 2009]

MANE transcript

NM_006397.3

Inheritance

AD, AR

ClinVar variants

P:51U:204B:147

Top phenotype

Aicardi-Goutieres syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr19:12,806,584-12,813,640

External References & Databases

Ensembl (ENSG00000104889)NCBI Gene (10535)OMIM (606034)HGNC:18518GenCCUniProt (O75792)AlphaFoldClinVar (RNASEH2A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~7.1 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Aicardi-Goutieres syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018866

Submitter: Orphanet

RNASEH2A-related type 1 interferonopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0700259

Submitter: ClinGen

RNASEH2A was first reported in relation to autosomal recessive Aicardi-Goutieres syndrome type 4 (OMIM: 606034) in 2006 (PMID: 16845400). RNASEH2A encodes the ribonuclease H2 subunit A, which comprises 299 amino acids. RNASEH enzymes endolytically cleave ribonucleotides from RNA:DNA duplexes, which occur during DNA replication, transcription and translation. RNASEH2 has been proposed to function in the removal of lagging strand Okazaki fragment RNA primers during DNA replication, as well as in the excision of single ribonucleotides from DNA:DNA duplexes (PMIDs: 21177854, 16845400). The described autosomal recessive RNASEH2A phenotype is considered to be a form of type 1 interferonopathy, which is defined as a condition in which increased type 1 interferon signaling leads to autoimmune and neurological disorders (MONDO: 0700259). These disorders are caused by variants in genes involved in nucleic acid metabolism, sensing, and the innate immune response. Individuals with biallelic variants in RNASEH2A can present with a range of symptoms of variable severity and age of onset, within the context of an autoimmune disease. At least eight unique variants (missense, splicing, nonsense) have been reported across 10 probands in 4 publications (PMIDs: 29239743, 23592335, 16845400, 24183309) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is thought to be loss of function. This gene-disease relationship is also supported by experimental evidence (model system studies, PMID: 26880576). A study by Pokatayev et al., 2016 showed that Rnaseh2aG37S/G37S knock-in mice demonstrate increased expression of IFN-stimulated genes and subsequent immune system activation. In summary, there is definitive evidence supporting the relationship between RNASEH2A and autosomal recessive RNASEH2A-related type 1 interferonopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic setting, and has been upheld over time. This classification was approached by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date July 10, 2024 (SOP Version 10).

Aicardi-Goutieres syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012472

Submitter: PanelApp Australia

Aicardi-Goutieres syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012472

Submitter: Labcorp Genetics (formerly Invitae)

Aicardi-Goutieres syndrome 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012472

Submitter: G2P

Clinical Genomic Database (CGD)

Aicardi-Goutieres syndrome 4AR

Manifestation: Cardiovascular; Gastrointestinal; Dermatologic; Cardiovascular; Hematologic; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 16845400; 17846997; 20301648Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RNASEH2A variants in ClinVar

7 Conditions Cataloged
Aicardi-Goutieres syndrome 4Total: 496
Inborn genetic diseasesTotal: 56
not providedTotal: 51
not specifiedTotal: 48
RNASEH2A-related disorderTotal: 28
Aicardi Goutieres syndromeTotal: 6
RNASEH2A-related type 1 interferonopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006397.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
1
clinvar
3
clinvar
138
clinvar
 143
missense
2
clinvar
11
clinvar
190
clinvar
9
clinvar
 212
nonsense
5
clinvar
4
clinvar
1
clinvar
 10
start loss
1
clinvar
 1
frameshift
10
clinvar
5
clinvar
6
clinvar
 21
splice donor/acceptor (+/-2bp)
11
clinvar
4
clinvar
 15
Total18332041470402

Highest pathogenic variant AF is 0.00007124669

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006397.3RefSeqNP_006388.28MANE Select
ENST00000221486.6EnsemblENSP00000221486.48MANE Select
ENST00000590121.2EnsemblENSP00000495087.14Standard
ENST00000646769.1EnsemblENSP00000495175.13Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • DNA replication - Homo sapiens (human)

Biological Process

  • DNA replication
  • mismatch repair
  • RNA catabolic process
  • DNA replication, removal of RNA primer
  • RNA phosphodiester bond hydrolysis, endonucleolytic

Molecular Function

  • RNA binding
  • RNA-DNA hybrid ribonuclease activity
  • ribonuclease activity
  • metal ion binding

Cellular Component

  • nucleoplasm
  • cytosol
  • ribonuclease H2 complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000221486
Coding exons
8
Length
7059
Individuals with no LoFs
125700
Homozygous LoFs
0
Heterozygous LoFs
48
Defined
125748
p
0.000191
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.1931711780.9590.00001161920
Missense (PolyPhen)6074.0490.81027831
Synonymous-0.5918477.41.090.00000527601
Loss of Function1.88613.50.4465.92e-7161

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00160.0016notable
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.000510.00051rare
European (Non-Finnish)0.0000530.000053rare
South Asian0.0000650.000065rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalytic subunit of RNase HII, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids. Participates in DNA replication, possibly by mediating the removal of lagging- strand Okazaki fragment RNA primers during DNA replication. Mediates the excision of single ribonucleotides from DNA:RNA duplexes. {ECO:0000269|PubMed:16845400, ECO:0000269|PubMed:21177858}.;
Disease
DISEASE: Aicardi-Goutieres syndrome 4 (AGS4) [MIM:610333]: A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. {ECO:0000269|PubMed:16845400, ECO:0000269|PubMed:17846997, ECO:0000269|PubMed:20131292}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.484

Intolerance Scores

LoFtool
0.254
RVIS EVS
-0.05
RVIS percentile EVS
50.01

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.896

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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