FAM149A

Chr 4

family with sequence similarity 149 member A

Also known as: MST119, MSTP119

NCBI Gene: 25854 ENSG00000109794 UniProt: A5PLN7

The protein encoded by this gene functions as a component of the nuclear envelope, specifically localizing to the inner nuclear membrane where it contributes to nuclear structure and organization. Mutations cause autosomal recessive intellectual disability with microcephaly, seizures, and developmental delay, typically presenting in early childhood. This gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely not tolerated.

Research

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.79

Clinical Summary— FAM149A

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.79LOEUF

pLI 0.000

Z-score 2.34

OE 0.49 (0.31–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.32Z-score

OE missense 1.05 (0.96–1.16)

310 obs / 294.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.49 (0.31–0.79)

0≤0.351.4

Missense OE?1.05 (0.96–1.16)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 12 / 24.5Missense obs/exp: 310 / 294.8Syn Z: -0.92

This gene — mechanism propensity

0.6646th %ile

GOF

0.74top 25%

LOF

0.4038th %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.