TMEM67

Chr 8AR

transmembrane protein 67

Also known as: JBTS6, MECKELIN, MKS3, NPHP11, TNEM67

NCBI Gene: 91147 ENSG00000164953 UniProt: Q5HYA8

The protein encoded by this gene localizes to the primary cilium and to the plasma membrane. The gene functions in centriole migration to the apical membrane and formation of the primary cilium. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Meckel syndrome type 3 (MKS3) and Joubert syndrome type 6 (JBTS6). [provided by RefSeq, Nov 2008]

Primary Disease Associations & Inheritance

?RHYNS syndromeMIM #602152

{Bardet-Biedl syndrome 14, modifier of}MIM #615991

COACH syndrome 1MIM #216360

Joubert syndrome 6MIM #610688

Meckel syndrome 3MIM #607361

Nephronophthisis 11MIM #613550

565

ClinVar variants

107

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— TMEM67

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Gene-Disease Validity (ClinGen)

ciliopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

107 Pathogenic / Likely Pathogenic· 202 VUS of 565 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.94LOEUF

pLI 0.000

Z-score 1.92

OE 0.74 (0.58–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.49Z-score

OE missense 0.94 (0.87–1.01)

483 obs / 514.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.74 (0.58–0.94)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.87–1.01)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.88

0≤1.21.6

LoF obs/exp: 46 / 62.3Missense obs/exp: 483 / 514.4Syn Z: 1.27

ClinVar Variant Classifications

565 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53

Likely Pathogenic54

VUS202

Likely Benign217

Benign9

Conflicting30

Pathogenic

Likely Pathogenic

202

VUS

217

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	10	23	0	53
Likely Pathogenic	27	20	7	0	54
VUS	5	170	26	1	202
Likely Benign	0	5	101	111	217
Benign	0	0	9	0	9
Conflicting	—				30
Total	52	205	166	112	565

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

View in ClinVar →

Protein Context — Lollipop Plot

TMEM67 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TMEM67-related nephronophthisis

definitive

ARUndeterminedUncertain

Dev. Disorders

G2P ↗

TMEM67-related COACH syndrome

definitive

ARLoss Of FunctionAbsent Gene Product

Dev. DisordersEye

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

TRANSMEMBRANE PROTEIN 67; TMEM67

MIM #609884 · *

?RHYNS syndrome

MIM #602152