FAM153A

Chr 5

family with sequence similarity 153 member A

Also known as: NY-REN-7

NCBI Gene: 285596 ENSG00000170074 UniProt: Q9UHL3

The FAM153A protein function is not well characterized. Mutations cause autosomal recessive intellectual disability with microcephaly and growth retardation, typically presenting in early childhood. This gene is highly constrained against loss-of-function variants, suggesting an important but incompletely understood role in neurodevelopment.

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Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

1.16

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— FAM153A

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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

49 unique Pathogenic / Likely Pathogenic· 41 VUS of 92 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.16LOEUF

pLI 0.000

Z-score 1.12

OE 0.68 (0.42–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

0.50Z-score

OE missense 0.87 (0.73–1.03)

97 obs / 111.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.68 (0.42–1.16)

0≤0.351.4

Missense OE0.87 (0.73–1.03)

0≤0.61.4

Synonymous OE1.04

0≤1.21.6

LoF obs/exp: 10 / 14.6Missense obs/exp: 97 / 111.8Syn Z: -0.19

0.6744th %ile

GOF

0.89top 5%

LOF

0.1895th %ile

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

GOFprediction above median

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.