RNASEH1

protein-coding

ribonuclease H1

Gene summary

This gene encodes an endonuclease that specifically degrades the RNA of RNA-DNA hybrids and plays a key role in DNA replication and repair. Alternate in-frame start codon initiation results in the production of alternate isoforms that are directed to the mitochondria or to the nucleus. The production of the mitochondrial isoform is modulated by an upstream open reading frame (uORF). Mutations in this gene have been found in individuals with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2. Alternative splicing results in additional coding and non-coding transcript variants. Pseudogenes of this gene have been defined on chromosomes 2 and 17. [provided by RefSeq, Jul 2017]

MANE transcript

NM_002936.6

Inheritance

AD, AR

ClinVar variants

P:6U:87B:76

Top phenotype

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive, 2

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr2:3,541,430-3,558,333

External References & Databases

Ensembl (ENSG00000171865)

Transcript & Mutation Effects

hg38 • Region Span ~16.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018002

Submitter: Orphanet

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014656

Submitter: Labcorp Genetics (formerly Invitae)

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014656

Submitter: PanelApp Australia

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between RNASEH1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of September 21, 2020. The RNASHE1 gene encodes ribonuclease H1, an endonuclease, present in both the nucleus and mitochondria, that digests the RNA component of RNA-DNA hybrids. However, the nucleus has a second ribonuclease (RNase H2) that mitochondria do not, therefore the RNase H1 enzyme plays a critical role in mitochondrial DNA replication and maintenance. The RNASEH1 gene has been reported only once in relation to autosomal recessive Leigh syndrome spectrum, in 2019 (PMID: 31271879). Of note, many individuals with RNASEH1-related disease have chronic progressive external ophthalmoplegia (CPEO) as well as a more generalized, cerebral, cerebellar, and brainstem atrophy distinct from what is seen in Leigh syndrome spectrum. Evidence supporting the gene-disease relationship between RNASEH1 and Leigh syndrome spectrum includes case-level data and experimental data. This curation included one variant identified in one case from one publication (PMID: 31271879). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, functional alternation in patient cells, and animal models (PMIDs: 28215579, 26094573, 12667461). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 21, 2020 (SOP Version 7).

Clinical Genomic Database (CGD)

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive, 2AR

Manifestation: Biochemical; Musculoskeletal; 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: 26094573

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RNASEH1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 183

Inborn genetic diseasesTotal: 39

RNASEH1-related disorderTotal: 21

not specifiedTotal: 13

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2Total: 7

Possible mitochondrial disorder - nuclear genesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002936.6. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	67 clinvar		70
missense	2 clinvar	1 clinvar	74 clinvar	9 clinvar		86
nonsense		1 clinvar	2 clinvar			3
start loss						0
frameshift		2 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	2	4	87	76	0	169

Highest pathogenic variant AF is 0.000017360013

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002936.6	RefSeq	NP_002927.2	8	MANE Select
ENST00000315212.4	Ensembl	ENSP00000313350.3	8	MANE Select
NM_001286834.3	RefSeq	NP_001273763.1	8	Standard
NM_001286837.3	RefSeq	NP_001273766.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

DNA replication - Homo sapiens (human)

Biological Process

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

Molecular Function

magnesium ion binding
nucleic acid binding
RNA binding
RNA-DNA hybrid ribonuclease activity
ribonuclease activity

Cellular Component

cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315212
Coding exons: 8
Length: 13824
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125748
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.107	167	171	0.977	0.00000975	1874
Missense (PolyPhen)		44	67.619	0.6507		775
Synonymous	-2.44	94	68.3	1.38	0.00000457	530
Loss of Function	2.32	6	16.0	0.374	8.50e-7	175

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00050	0.00049	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Endonuclease that specifically degrades the RNA of RNA- DNA hybrids (PubMed:10497183). Plays a role in RNA polymerase II (RNAp II) transcription termination by degrading R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site and behind the elongating RNAp II (PubMed:21700224). {ECO:0000269|PubMed:10497183, ECO:0000269|PubMed:21700224}.;

Recessive Scores

pRec: 0.117

Intolerance Scores

LoFtool: 0.434
RVIS EVS: -0.74
RVIS percentile EVS: 13.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.151

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium