NSUN2

protein-coding

NOP2/Sun RNA methyltransferase 2, the group of NOP2/Sun RNA methyltransferase family

Gene summary

This gene encodes a methyltransferase that catalyzes the methylation of cytosine to 5-methylcytosine (m5C) at position 34 of intron-containing tRNA(Leu)(CAA) precursors. This modification is necessary to stabilize the anticodon-codon pairing and correctly translate the mRNA. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Mar 2011]

Previous symbols:

MRT5

MANE transcript

NM_017755.6

Inheritance

ClinVar variants

P:57U:231B:153

Top phenotype

Intellectual developmental disorder, autosomal recessive 5

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr5:6,599,239-6,633,291

External References & Databases

Ensembl (ENSG00000037474)

Transcript & Mutation Effects

hg38 • Region Span ~34.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012613

Submitter: PanelApp Australia

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000508

Submitter: ClinGen

*NSUN2* was first reported in relation to autosomal recessive syndromic intellectual disability in 2012 (Abbasi-Moheb et al., PMID: 22541559; Khan et al., PMID: 22541562; Martinez et al., PMID: 22577224). The clinical presentation includes global developmental delay, intellectual disability, microcephaly, short stature, delayed puberty, infertility, dysmorphic facial features and a wide-range of ocular-related abnormalities. Twelve *NSUN2* variants (splice site, nonsense, frameshift, missense) that have been reported in 11 probands are included in this curation. Variants in this gene segregated with disease in 14 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Both consanguineous and non-consanguineous families from different ethnicities have been reported. The mechanism for disease is biallelic loss of function. Of note, an individual with a homozygous frameshift variant in *NSUN2*, scored here, was described as having facial features reminiscent of Noonan syndrome (PMID: 24102521). This assertion was assessed separately by the ClinGen RASopathy Gene Curation Expert Panel and the relationship between *NSUN2* and RASopathies was disputed. *NSUN2* encodes an RNA methyltransferase that modifies transfer RNAs crucial for protein synthesis. Experimental evidence supporting this gene-disease relationship includes knockout models in mice (PMIDs: 22144916, 25063673, 3438972) and drosophila (PMID: 22541559). In summary, there is definitive evidence to support the relationship between *NSUN2* and syndromic intellectual disability. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 6, 2019. It was re-evaluated on October 18, 2023. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of new literature (SOP Version 9).

intellectual developmental disorder, autosomal recessive 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012613

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 5MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012613

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012613

Submitter: G2P

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

RASopathyNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0021060

Submitter: ClinGen

NSUN2 was first reported in relation to autosomal recessive RASopathies in 2012 (Martinez et al., PMID 22577224). At least 2 variants (e.g. frameshift, splice site) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, and experimental data but only the mouse model supporting this association could be scored (PMIDs: 24102521, 22144916, 22577224). Variants in this gene have been reported in at least 2 probands in 2 publications (PMIDs 22577224, 24102521). Variants in this gene segregated with disease in 2 additional family members. This gene-disease association is supported by a mouse model indicating that homozygous deletion of the NSUN2 gene caused short stature and craniofacial anomalies (PMIDs: 22144916). However, the patients reported with NSUN2 variants did not possess convincing clinical features consistent with Noonan syndrome, despite the reports from Fahiminiya et al. 2014 suggesting that the condition was Noonan-like. Therefore, using the expert judgment of the ClinGen RASopathy Gene Curation Expert Panel these cases were not scored. In summary, the relationship between NSUN2 and autosomal recessive RASopathies is disputed. More evidence is needed to either support or refute the role NSUN2 plays in this disease. Additionally, this gene will be separately assessed by the ClinGen ID/Autism Gene Curation Expert Panel for complex neurodevelopmental disorder. This classification was approved by the ClinGen RASopathy Gene Curation Expert Panel on 2/4/2019 (SOP Version 5).

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 5AR

Manifestation: Craniofacial; 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: 22541559; 22541562; 22577224

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NSUN2 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 393

Inborn genetic diseasesTotal: 179

Intellectual disability, autosomal recessive 5Total: 87

not specifiedTotal: 67

NSUN2-related disorderTotal: 10

Intellectual disabilityTotal: 8

NSUN2-related disordersTotal: 5

PhenylketonuriaTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017755.6. 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			7 clinvar	134 clinvar	1 clinvar	142
missense	1 clinvar	5 clinvar	209 clinvar	14 clinvar	4 clinvar	233
nonsense	10 clinvar	7 clinvar	3 clinvar			20
start loss						0
frameshift	15 clinvar	10 clinvar	4 clinvar			29
splice donor/acceptor (+/-2bp)	3 clinvar	6 clinvar	8 clinvar			17
Total	29	28	231	148	5	441

Highest pathogenic variant AF is 0.000030872267

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017755.6	RefSeq	NP_060225.4	19	MANE Select
ENST00000264670.11	Ensembl	ENSP00000264670.6	19	MANE Select
NM_001193455.2	RefSeq	NP_001180384.1	18	Standard
ENST00000504374.5	Ensembl	ENSP00000421783.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

tRNA modification in the nucleus and cytosol
tRNA processing
Metabolism of RNA
Aurora B signaling

Biological Process

tRNA modification
spermatid development
tRNA methylation
meiotic cell cycle checkpoint
hair follicle maturation

Molecular Function

tRNA binding
RNA binding
methyltransferase activity
tRNA (cytosine-5-)-methyltransferase activity

Cellular Component

nucleus
nucleoplasm
nucleolus
cytoplasm
spindle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264670
Coding exons: 19
Length: 34053
Individuals with no LoFs: 125707
Homozygous LoFs: 0
Heterozygous LoFs: 41
Defined: 125748
p: 0.000163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0340	428	430	0.995	0.0000232	5039
Missense (PolyPhen)		131	162.89	0.80423		1882
Synonymous	-0.159	165	162	1.02	0.00000936	1417
Loss of Function	3.93	14	41.2	0.340	0.00000215	481

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00044	0.00044	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: RNA methyltransferase that methylates tRNAs, and possibly RNA polymerase III transcripts. Methylates cytosine to 5- methylcytosine (m5C) at positions 34 and 48 of intron-containing tRNA(Leu)(CAA) precursors, and at positions 48, 49 and 50 of tRNA(Gly)(GCC) precursors. May act downstream of Myc to regulate epidermal cell growth and proliferation. Required for proper spindle assembly and chromosome segregation, independently of its methyltransferase activity. {ECO:0000269|PubMed:17071714, ECO:0000269|PubMed:19596847, ECO:0000269|PubMed:22995836}.;
Disease: DISEASE: Mental retardation, autosomal recessive 5 (MRT5) [MIM:611091]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:22541559, ECO:0000269|PubMed:22541562}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.188

Intolerance Scores

LoFtool: 0.873
RVIS EVS: -1
RVIS percentile EVS: 8.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.905

Gene Damage Prediction

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