SMG6

Chr 17

SMG6 nonsense mediated mRNA decay factor

Also known as: C17orf31, EST1A, SMG-6, hEST1A, hSMG5/7a

NCBI Gene: 23293 ENSG00000070366 UniProt: Q86US8 OMIM: 610963

The encoded protein functions as a component of the telomerase ribonucleoprotein complex essential for chromosome end replication and maintenance, and provides endonuclease activity in the nonsense-mediated mRNA decay pathway. Mutations cause autosomal recessive intellectual developmental disorder with cardiac arrhythmias, dysmorphism, and skeletal malformations. This gene is highly constrained against loss-of-function variants (pLI 0.98, LOEUF 0.30), indicating intolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a component of the telomerase ribonucleoprotein complex responsible for the replication and maintenance of chromosome ends. The encoded protein also plays a role in the nonsense-mediated mRNA decay (NMD) pathway, providing the endonuclease activity near the premature translation termination codon that is needed to initiate NMD. Alternatively spliced transcript variants encoding distinct protein isoforms have been described. [provided by RefSeq, Feb 2014]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.30

Clinical Summary— SMG6

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.30LOEUF

pLI 0.982

Z-score 6.10

OE 0.18 (0.12–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.18Z-score

OE missense 0.98 (0.93–1.04)

820 obs / 834.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.12–0.30)

0≤0.351.4

Missense OE?0.98 (0.93–1.04)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 12 / 65.1Missense obs/exp: 820 / 834.5Syn Z: -2.28

This gene — mechanism propensity

0.2898th %ile

GOF

0.2597th %ile

LOF

0.74top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.30

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.