8-93765617-A-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153704.6(TMEM67):c.622A>T(p.Arg208Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000298 in 1,613,342 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_153704.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM67 | NM_153704.6 | c.622A>T | p.Arg208Ter | stop_gained | 6/28 | ENST00000453321.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM67 | ENST00000453321.8 | c.622A>T | p.Arg208Ter | stop_gained | 6/28 | 1 | NM_153704.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000236 AC: 36AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000175 AC: 44AN: 251386Hom.: 0 AF XY: 0.000191 AC XY: 26AN XY: 135876
GnomAD4 exome AF: 0.000304 AC: 444AN: 1461104Hom.: 0 Cov.: 29 AF XY: 0.000300 AC XY: 218AN XY: 726958
GnomAD4 genome AF: 0.000236 AC: 36AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74380
ClinVar
Submissions by phenotype
not provided Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 25, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 04, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19508969, 17397051, 31974414, 23352055, 26092869, 23559409, 26729329, 25525159, 17377820, 21866095, 25920555, 28973083, 29891882, 28680603, 28497568, 29146704, 34426522, 31589614) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Joubert syndrome 6 Pathogenic:4
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 16, 2014 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 10, 2021 | This variant was identified as compound heterozygous with NM_153704.6:c.2374A>G._x000D_ Criteria applied: PVS1, PS4 - |
RHYNS syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Sep 11, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP5. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2009 | - - |
TMEM67-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The TMEM67 c.622A>T (p.Arg208Ter) variant is a stop-gained variant and is predicted result in premature termination of the TMEM67 protein. Across a selection of available literature, the p.Arg208Ter variant has been identified in 12 patients with a phenotype of nephronophthisis, Joubert syndrome, or Meckel syndrome, including in a compound heterozygous state in nine patients and in a heterozygous state in three affected patients in whom a second variant was not identified, and in a heterozygous state in seven unaffected family members (Consugar et al. 2007; Khaddour et al. 2007; Otto et al. 2009; Halbritter et al. 2013). The p.Arg208Ter variant was absent from 388 controls and is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of stop-gained variants, the p.Arg208Ter variant is classified as pathogenic for TMEM67-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant results in a c.379A>T (p.Arg127Ter) change in an alternate TMEM67 transcript NM_001142301. This gene is also known as MKS3 in the literature (PMID: 17397051). This nonsense variant found in exon 7 of 28 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in the compound heterozygous state in individuals with Joubert Syndrome, Meckel-Gruber syndrome, and nephronophthisis (PMID: 17397051, 21866095, 26092869, 17377820, 23559409). Loss-of-function variation in TMEM67 has been reported in affected individuals in the literature (PMID: 17397051, 21866095, 26092869, 17377820, 23559409). The c.622A>T (p.Arg208Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.017% (49/282,794). Based on the available evidence, the c.622A>T (p.Arg208Ter) variant is classified as Pathogenic. - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Arg208*) in the TMEM67 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449, 23559409). This variant is present in population databases (rs137853108, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with Joubert syndrome, Meckel-Gruber syndrome, and/or nephronophthisis-related ciliopathies (PMID: 17377820, 17397051, 21866095, 23559409, 26092869). ClinVar contains an entry for this variant (Variation ID: 1376). For these reasons, this variant has been classified as Pathogenic. - |
Meckel syndrome, type 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2009 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2023 | The c.622A>T (p.R208*) alteration, located in exon 6 (coding exon 6) of the TMEM67 gene, consists of an A to T substitution at nucleotide position 622. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 208. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.017% (49/282794) total alleles studied. The highest observed frequency was 0.037% (48/129126) of European (non-Finnish) alleles. This variant has been detected in conjunction with other variants in the TMEM67 gene in multiple individuals diagnosed with clinical features associated with TMEM67-related ciliopathies; however, the phase of the two variants is either unspecified or confirmed in trans (opposite chromosome) (Otto, 2009; Khaddour, 2007; Chaki, 2011; Szymanska, 2012; Bachmann-Gagescu, 2015; Summers, 2017; Vogel, 2017; Meng, 2017). Based on the available evidence, this alteration is classified as pathogenic. - |
Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 26, 2022 | - - |
Joubert syndrome and related disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 09, 2022 | Variant summary: TMEM67 c.622A>T (p.Arg208X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00018 in 251386 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders (0.00018 vs 0.0018), allowing no conclusion about variant significance. c.622A>T has been reported in the literature in multiple individuals affected with Joubert Syndrome, Meckel-Gruber syndrome and nephronophthisis-related ciliopathies (e.g. Consugar_2007, Halbritter_2013, Fleming_2017). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at