NSUN5

Chr 7

NOP2/Sun RNA methyltransferase 5

Also known as: NOL1, NOL1R, NSUN5A, WBSCR20, WBSCR20A, p120, p120(NOL1)

NCBI Gene: 55695 ENSG00000130305 OMIM: 615732

This protein is a methyltransferase that specifically methylates cytosine in 28S ribosomal RNA to promote protein translation and is required for corpus callosum and cerebral cortex development. Biallelic mutations cause autosomal recessive intellectual disability with corpus callosum abnormalities and cortical malformations. The gene is extremely intolerant to loss-of-function variants (pLI near 1), indicating that heterozygous loss alone is likely damaging, though disease manifestation requires biallelic variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of an evolutionarily conserved family of proteins that may function as methyltransferases. This gene is located in a larger region of chromosome 7 that is deleted in Williams-Beuren syndrome, a multisystem developmental disorder. There are two pseudogenes for this gene located in the same region of chromosome 7. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.30

Clinical Summary— NSUN5

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

75 VUS of 95 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.30LOEUF

pLI 0.000

Z-score 0.47

OE 0.89 (0.63–1.30)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.17Z-score

OE missense 0.97 (0.88–1.07)

291 obs / 299.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.89 (0.63–1.30)

0≤0.351.4

Missense OE?0.97 (0.88–1.07)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 20 / 22.4Missense obs/exp: 291 / 299.5Syn Z: -0.74

This gene — mechanism propensity

0.6647th %ile

GOF

0.5072th %ile

LOF

0.3356th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

95 submitted variants in ClinVar

ClinVar

Classification Summary

VUS75

Likely Benign14

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	75	0	75
Likely Benign	13	1	14
Benign	0	0	0
Total	88	1	89

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

129 pathogenic / likely-pathogenic (of 138) ClinVar copy-number / structural variants overlap NSUN5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →