TMTC3

protein-coding

transmembrane O-mannosyltransferase targeting cadherins 3, the group of Transmembrane and tetratricopeptide repeat containing|Tetratricopeptide repeat domain containing

Gene summary

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

MANE transcript

NM_181783.4

Inheritance

AR, AD

ClinVar variants

P:21U:156B:61

Top phenotype

Lissencephaly 8

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr12:88,142,296-88,199,887

External References & Databases

Ensembl (ENSG00000139324)

Transcript & Mutation Effects

hg38 • Region Span ~57.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lissencephaly 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014992

Submitter: Labcorp Genetics (formerly Invitae)

lissencephaly 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014992

Submitter: G2P

periventricular nodular heterotopiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020341

Submitter: Orphanet

lissencephaly 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014992

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Lissencephaly 8AR

Manifestation: Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 27773428

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMTC3 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 170

Inborn genetic diseasesTotal: 100

Lissencephaly 8Total: 27

TMTC3-related disorderTotal: 19

not specifiedTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_181783.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	49 clinvar		53
missense	1 clinvar	2 clinvar	144 clinvar	8 clinvar	4 clinvar	159
nonsense	3 clinvar	3 clinvar	1 clinvar			7
start loss	1 clinvar					1
frameshift	4 clinvar	5 clinvar	3 clinvar			12
splice donor/acceptor (+/-2bp)		2 clinvar	4 clinvar			6
Total	9	12	156	57	4	238

Highest pathogenic variant AF is 0.000026035661

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_181783.4	RefSeq	NP_861448.2	13	MANE Select
ENST00000266712.11	Ensembl	ENSP00000266712.6	13	MANE Select
NM_001366574.1	RefSeq	NP_001353503.1	13	Standard
NM_001366579.1	RefSeq	NP_001353508.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

response to endoplasmic reticulum stress
positive regulation of proteasomal protein catabolic process

Molecular Function

protein binding

Cellular Component

endoplasmic reticulum
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000266712
Coding exons: 13
Length: 57592
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 55
Defined: 125744
p: 0.000219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.62	364	462	0.788	0.0000217	5996
Missense (PolyPhen)		97	143.06	0.67804		1772
Synonymous	1.11	142	160	0.888	0.00000729	1716
Loss of Function	3.76	15	41.0	0.366	0.00000224	552

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00050	0.00043	rare
Latino/Admixed American	0.00015	0.00012	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00013	0.00011	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00024	0.00024	rare
South Asian	0.00028	0.00026	rare
Other	0.00036	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the positive regulation of proteasomal protein degradation in the endoplasmic reticulum (ER), and the control of ER stress response. {ECO:0000269|PubMed:21603654}.;
Disease: DISEASE: Lissencephaly 8 (LIS8) [MIM:617255]: A form of lissencephaly, a disorder of cortical development characterized by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six-layered cortex. LIS8 patients manifest delayed psychomotor development, intellectual disability with poor or absent speech, early-onset refractory seizures, hypotonia, cortical gyral abnormalities, and hypoplasia of the corpus callosum, brainstem and cerebellum. LIS8 inheritance is autosomal recessive. {ECO:0000269|PubMed:27773428}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.203

Intolerance Scores

LoFtool: 0.780
RVIS EVS: 0.13
RVIS percentile EVS: 63.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.687

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium