TLCD3A

Chr 17

TLC domain containing 3A

Also known as: CT120, FAM57A

NCBI Gene: 79850 ENSG00000167695 UniProt: Q8TBR7 OMIM: 611627

The TLCD3A protein is a membrane-associated protein involved in amino acid transport and glutathione metabolism through interactions with solute carrier proteins and gamma-glutamyltranspeptidase-like enzymes. Mutations in this gene have not been definitively associated with recognized pediatric neurological disorders based on the available information. The gene shows moderate constraint against loss-of-function mutations (LOEUF 0.649), suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq

The protein encoded by this gene is a membrane-associated protein that promotes lung carcinogenesis. The encoded protein may be involved in amino acid transport and glutathione metabolism since it can interact with a solute carrier family member (SLC3A2) and an isoform of gamma-glutamyltranspeptidase-like 3. An alternatively spliced variant encoding a protein that lacks a 32 aa internal segment showed the opposite effect, inhibiting lung cancer cell growth. Knockdown of this gene also inhibited lung carcinogenesis and tumor cell growth. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.65

Clinical Summary— TLCD3A

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

52 VUS of 68 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.256

Z-score 2.40

OE 0.25 (0.11–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.22Z-score

OE missense 1.05 (0.92–1.21)

146 obs / 138.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.25 (0.11–0.65)

0≤0.351.4

Missense OE?1.05 (0.92–1.21)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 3 / 11.9Missense obs/exp: 146 / 138.7Syn Z: -0.46

This gene — mechanism propensity

0.80top 25%

GOF

0.74top 25%

LOF

0.2190th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

68 submitted variants in ClinVar

ClinVar

Classification Summary

VUS52

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	1	51	52
Likely Benign	0	5	5
Benign	0	0	0
Total	1	56	57

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

View in ClinVar →

62 pathogenic / likely-pathogenic (of 116) ClinVar copy-number / structural variants overlap TLCD3A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →