rs386834182
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_153704.6(TMEM67):c.1319G>A(p.Arg440Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000818 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000086 ( 0 hom. )
Consequence
TMEM67
NM_153704.6 missense
NM_153704.6 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 6.76
Genes affected
TMEM67 (HGNC:28396): (transmembrane protein 67) 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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.886
PP5
Variant 8-93786253-G-A is Pathogenic according to our data. Variant chr8-93786253-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93786253-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-93786253-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM67 | NM_153704.6 | c.1319G>A | p.Arg440Gln | missense_variant | 13/28 | ENST00000453321.8 | NP_714915.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMEM67 | ENST00000453321.8 | c.1319G>A | p.Arg440Gln | missense_variant | 13/28 | 1 | NM_153704.6 | ENSP00000389998.3 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152052Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251216Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135786
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GnomAD4 exome AF: 0.0000855 AC: 125AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.0000756 AC XY: 55AN XY: 727196
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74386
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 02, 2024 | Published functional studies in a knockout mouse model demonstrate a damaging effect with abolished binding to Wnt5a (PMID: 26035863); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17377820, 19058225, 20232449, 26729329, 26275793, 19466712, 30266093, 17397051, 36090483, 26035863) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 01, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 06, 2023 | PP1_strong, PP3, PM2, PM3, PS3_supporting, PS4_moderate - |
Meckel syndrome, type 3 Pathogenic:2
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 440 of the TMEM67 protein (p.Arg440Gln). This variant is present in population databases (rs386834182, gnomAD 0.01%). This missense change has been observed in individuals with Meckel–Gruber syndrome (PMID: 17377820, 17397051). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56764). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Joubert syndrome and related disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2021 | Variant summary: TMEM67 c.1319G>A (p.Arg440Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251216 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TMEM67 causing Joubert Syndrome and Related Disorders (0.0018), allowing no conclusion about variant significance. The variant, c.1319G>A, has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Joubert Syndrome and Related Disorders (Consugar_2007, Khaddour_2007, Tallila_2009, Brancati_2009, Iannicelli_2010), including segregation evidence in some families (Consugar_2007, Tallila_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the variant abolished binding to Wnt5a, and failed to restore the de-regulated Wnt/beta-catenin signaling in Tmem67 -/- mouse embryonic fibroblasts (Abdelhamed_2015).Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS, likely pathogenic or pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;M;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;N
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;T
Sift4G
Pathogenic
D;D;D;T
Polyphen
1.0
.;D;.;.
Vest4
0.93, 0.89
MVP
MPC
0.61
ClinPred
D
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at