PRAMEF1

Chr 1

PRAME family member 1

NCBI Gene: 65121 ENSG00000116721 UniProt: O95521 OMIM: 621623

PRAMEF1 encodes a protein that belongs to the PRAME gene family and may function in reproductive tissues during development. This gene is extremely intolerant to loss-of-function variants (pLI near 0), but no definitive human disease associations have been established in the provided data. The clinical significance of PRAMEF1 variants in pediatric neurological disorders remains unclear based on current evidence.

OMIM ResearchSummary from RefSeq

This gene is a member of the PRAME (preferentially expressed antigen of melanoma) gene family which is expressed in many cancers but may function in reproductive tissues during development. Alternative promoter usage generates two transcript variants, which encode different isoforms. [provided by RefSeq, Jun 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.88

Clinical Summary— PRAMEF1

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

89 VUS of 106 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?

1.88LOEUF

pLI 0.000

Z-score -1.03

OE 1.35 (0.88–1.88)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.13Z-score

OE missense 1.39 (1.27–1.52)

326 obs / 234.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.35 (0.88–1.88)

0≤0.351.4

Missense OE?1.39 (1.27–1.52)

0≤0.61.4

Synonymous OE?1.43

0≤1.21.6

LoF obs/exp: 14 / 10.4Missense obs/exp: 326 / 234.2Syn Z: -3.35

This gene — mechanism propensity

0.6936th %ile

GOF

0.6639th %ile

LOF

0.2289th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

106 submitted variants in ClinVar

ClinVar

Classification Summary

VUS89

Likely Benign12

Benign3

Conflicting1

VUS

Likely Benign

Benign

Conflicting

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	0	89	0	0	89
Likely Benign	0	5	0	7	12
Benign	0	1	0	2	3
Conflicting	—				1
Total	0	95	0	9	105

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap PRAMEF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →