TMTC4

protein-coding

transmembrane O-mannosyltransferase targeting cadherins 4, the group of Tetratricopeptide repeat domain containing|Transmembrane and tetratricopeptide repeat containing

Gene summary

This gene encodes a transmembrane protein that belongs to family of proteins containing an N-terminal transmembrane domain and a C-terminal tetratricopeptide repeat (TPR) domain. TPR domains mediate protein-protein interactions in various cellular processes, such as synaptic vesicle fusion, protein folding, and protein translocation. A pseudogene of this gene has been defined on chromosome 5. [provided by RefSeq, Apr 2017]

MANE transcript

NM_032813.5

Inheritance

ClinVar variants

P:2U:142B:12

Top phenotype

Deafness, autosomal recessive 122

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr13:100,603,625-100,675,093

External References & Databases

Ensembl (ENSG00000125247)

Transcript & Mutation Effects

hg38 • Region Span ~71.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 122AR

Manifestation: Audiologic/Otolaryngologic

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: 37943620

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMTC4 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 135

TMTC4-related conditionTotal: 4

Hearing loss, autosomal recessive 122Total: 3

not providedTotal: 2

Worster-Drought syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032813.5. 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			3 clinvar	3 clinvar		6
missense	2 clinvar		132 clinvar	9 clinvar		143
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	2	0	142	12	0	156

Highest pathogenic variant AF is 0.000004338212

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032813.5	RefSeq	NP_116202.2	18	MANE Select
ENST00000342624.10	Ensembl	ENSP00000343871.5	18	MANE Select
NM_001079669.4	RefSeq	NP_001073137.1	17	Standard
NM_001286453.3	RefSeq	NP_001273382.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Cellular Component

integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342624
Coding exons: 18
Length: 71167
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 59
Defined: 125748
p: 0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.185	428	439	0.975	0.0000256	4947
Missense (PolyPhen)		122	124.42	0.98056		1392
Synonymous	0.0400	189	190	0.996	0.0000123	1520
Loss of Function	2.61	20	37.1	0.538	0.00000166	450

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00057	0.00055	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00028	0.00027	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00019	0.00019	rare
South Asian	0.00024	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.104

Intolerance Scores

LoFtool: 0.482
RVIS EVS: -0.73
RVIS percentile EVS: 14.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.428

Gene Damage Prediction

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