NOMO3

Chr 16

NODAL modulator 3

Also known as: Nomo

NCBI Gene: 408050 ENSG00000103226 UniProt: P69849 OMIM: 609159

NOMO3 encodes a component of the multi-pass translocon complex that mediates insertion of multi-pass membrane proteins into cellular membranes, working alongside the SEC61 complex during protein insertion. The gene is not well-established as a cause of human disease, with loss-of-function variants appearing to be well-tolerated based on population constraint metrics. NOMO3 is part of a highly duplicated gene family on chromosome 16, which may provide functional redundancy.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein originally thought to be related to the collagenase gene family. This gene is one of three highly similar genes in a duplicated region on the short arm of chromosome 16. These three genes encode closely related proteins that may have the same function. The protein encoded by one of these genes has been identified as part of a protein complex that participates in the Nodal signaling pathway during vertebrate development. Mutations in ABCC6, which is located nearby, rather than mutations in this gene are associated with pseudoxanthoma elasticum. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.81

Clinical Summary— NOMO3

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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

70 VUS of 79 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?

0.81LOEUF

pLI 0.000

Z-score 2.22

OE 0.48 (0.29–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.11Z-score

OE missense 0.79 (0.70–0.90)

174 obs / 220.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.29–0.81)

0≤0.351.4

Missense OE?0.79 (0.70–0.90)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 10 / 20.9Missense obs/exp: 174 / 220.5Syn Z: 0.77

This gene — mechanism propensity

0.6355th %ile

GOF

0.6150th %ile

LOF

0.3259th %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

79 submitted variants in ClinVar

ClinVar

Classification Summary

VUS70

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	68	1	0	70
Likely Benign	0	2	0	2	4
Benign	0	0	0	0	0
Total	1	70	1	2	74

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

View in ClinVar →

157 pathogenic / likely-pathogenic (of 285) ClinVar copy-number / structural variants overlap NOMO3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →