SMG1

Chr 16

SMG1 nonsense mediated mRNA decay associated PI3K related kinase

Also known as: 61E3.4, ATX, LIP

NCBI Gene: 23049 ENSG00000157106 UniProt: Q96Q15 OMIM: 607032

This gene encodes a serine/threonine protein kinase that phosphorylates UPF1 to regulate nonsense-mediated mRNA decay and also functions in DNA damage response by phosphorylating p53. Mutations cause primary microcephaly with intellectual disability and developmental delay, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants, indicating that complete loss of SMG1 function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein involved in nonsense-mediated mRNA decay (NMD) as part of the mRNA surveillance complex. The protein has kinase activity and is thought to function in NMD by phosphorylating the regulator of nonsense transcripts 1 protein. Alternatively spliced transcript variants have been described, but their full-length nature has yet to be determined. [provided by RefSeq, Mar 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.05

Clinical Summary— SMG1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

25 VUS of 96 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.05LOEUF

pLI 1.000

Z-score 11.88

OE 0.02 (0.01–0.05)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.30Z-score

OE missense 0.78 (0.74–0.81)

1372 obs / 1761.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.05)

0≤0.351.4

Missense OE?0.78 (0.74–0.81)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 4 / 172.4Missense obs/exp: 1372 / 1761.5Syn Z: -2.76

This gene — mechanism propensity

0.2499th %ile

GOF

0.2198th %ile

LOF

0.78top 5%

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

LOFprediction above median · LOEUF 0.05

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

ClinVar Variant Classifications

96 submitted variants in ClinVar

ClinVar

Classification Summary

VUS25

Likely Benign9

Benign4

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	24	0	1	25
Likely Benign	2	1	6	9
Benign	2	0	2	4
Total	28	1	9	38

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap SMG1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →