rs765468645
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153704.6(TMEM67):c.514C>T(p.Arg172Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,610,892 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 (★★). 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.514C>T | p.Arg172Ter | stop_gained | 5/28 | ENST00000453321.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM67 | ENST00000453321.8 | c.514C>T | p.Arg172Ter | stop_gained | 5/28 | 1 | NM_153704.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151948Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251270Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135866
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1458944Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 725822
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151948Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74188
ClinVar
Submissions by phenotype
Meckel syndrome, type 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Jun 23, 2023 | The heterozygous variant c.514C>T (p.Arg172*) has been identified on couple carrier screening. The couple has a bad obstetric history. This variant can be associated with the fetal phenotype of renal cysts and occipital encephalocele in the previous fetus. This stop gain variant is predicted to cause NMD in the gene TMEM67 where loss of function is a known mechanism (PVS1_very strong). 86 pathogenic null variants have been reported in this gene so far. The population frequency in gnomAD (aggregated) is 0.0011% (PM2_moderate). This has been previously reported PMID 26729329 (PP5_supporting). - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2023 | This variant is present in population databases (rs765468645, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg172*) 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 premature translational stop signal has been observed in individual(s) with Meckel-Gruber syndrome (PMID: 26729329). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 506012). - |
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 | Mar 19, 2022 | - - |
Meckel-Gruber syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 31, 2018 | The p.Arg91X (NM_001142301.1 c.271C>T) (also described as NM_153704.5:c.514C>T p .Arg172X) variant in TMEM67 has been reported in 1 compound heterozygous individ ual with Meckel syndrome (Matson 2016). It has been identified in 1/24020 Africa n chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.o rg; rs765468645). This nonsense variant leads to a premature termination codon a t position 91, which is predicted to lead to a truncated or absent protein. Bial lelic loss of function of the TMEM67 gene is an established disease mechanism in Meckel syndrome. This alteration is then predicted to lead to a truncated or ab sent protein. In summary, although additional studies are required to fully esta blish its clinical significance, the p.Arg91X variant is likely pathogenic for M eckel syndrome in an autosomal recessive manner based on a predicted variant eff ect and its occurrence in an affected individual. - |
Nystagmus;C0240063:Iris coloboma;C1840379:Cerebellar vermis hypoplasia;C1858120:Generalized hypotonia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at