TMTC3

Chr 12AR

transmembrane O-mannosyltransferase targeting cadherins 3

Also known as: LIS8, SMILE

NCBI Gene: 160418 ENSG00000139324 UniProt: Q6ZXV5 OMIM: 617218

This protein functions as an O-mannosyl-transferase that transfers mannose residues to serine or threonine residues, primarily on cadherin superfamily proteins, and regulates proteasomal protein degradation in the endoplasmic reticulum. Mutations cause autosomal recessive lissencephaly 8, a severe brain malformation disorder affecting cortical development. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.56), consistent with its role in essential cellular glycosylation processes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that belongs to the transmembrane and tetratricopeptide repeat-containing protein family. [provided by RefSeq, May 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.561 OMIM phenotype

Clinical Summary— TMTC3

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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

20 unique Pathogenic / Likely Pathogenic· 157 VUS of 297 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.000

Z-score 3.76

OE 0.37 (0.24–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.62Z-score

OE missense 0.79 (0.72–0.86)

364 obs / 461.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.24–0.56)

0≤0.351.4

Missense OE?0.79 (0.72–0.86)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 15 / 41.0Missense obs/exp: 364 / 461.7Syn Z: 1.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTMTC3-related cobblestone lissencephalyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.76top 25%

GOF

0.7029th %ile

LOF

0.2679th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

297 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic10

VUS157

Likely Benign84

Benign20

Conflicting2

Pathogenic

Likely Pathogenic

157

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	2	1	0	10
Likely Pathogenic	8	2	0	0	10
VUS	3	141	9	4	157
Likely Benign	0	7	31	46	84
Benign	0	5	15	0	20
Conflicting	—				2
Total	18	157	56	50	283

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap TMTC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →