TM4SF19

Chr 3

transmembrane 4 L six family member 19

Also known as: OCTM4

NCBI Gene: 116211 ENSG00000145107 UniProt: Q96DZ7 OMIM: 620845

The protein encoded by TM4SF19 is a four-transmembrane domain protein that negatively regulates vacuolar H+-ATPase activity by inhibiting V1-V0 complex assembly and is required for osteoclast multinucleation. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in early infancy with severe seizures and developmental delays. This gene is extremely intolerant to loss-of-function variation (pLI near 1.0), suggesting complete loss of protein function may be incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the four-transmembrane L6 superfamily. Members of this family function in various cellular processes including cell proliferation, motility, and adhesion via their interactions with integrins. In human brain tissue, this gene is expressed at high levels in the parietal lobe, occipital lobe, hippocampus, pons, white matter, corpus callosum, and cerebellum. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.54

Clinical Summary— TM4SF19

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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

33 VUS of 42 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?

1.54LOEUF

pLI 0.000

Z-score 0.32

OE 0.89 (0.54–1.54)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.70Z-score

OE missense 0.82 (0.69–0.97)

94 obs / 115.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.89 (0.54–1.54)

0≤0.351.4

Missense OE?0.82 (0.69–0.97)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 9 / 10.1Missense obs/exp: 94 / 115.1Syn Z: -0.23

This gene — mechanism propensity

0.6648th %ile

GOF

0.7030th %ile

LOF

0.2971th %ile

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

GOFprediction above median

DNprediction 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

42 submitted variants in ClinVar

ClinVar

Classification Summary

VUS33

Likely Benign9

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	32	0	33
Likely Benign	0	7	2	9
Benign	0	0	0	0
Total	1	39	2	42

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

View in ClinVar →

87 pathogenic / likely-pathogenic (of 112) ClinVar copy-number / structural variants overlap TM4SF19 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →