chr8-93786256-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate
The NM_153704.6(TMEM67):c.1322G>T(p.Arg441Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,752 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R441C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_153704.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM67 | NM_153704.6 | c.1322G>T | p.Arg441Leu | missense_variant | 13/28 | ENST00000453321.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM67 | ENST00000453321.8 | c.1322G>T | p.Arg441Leu | missense_variant | 13/28 | 1 | NM_153704.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152038Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461714Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727146
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152038Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74260
ClinVar
Submissions by phenotype
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 22, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p. Arg441 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19574260, 23351400). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 56765). This missense change has been observed in individual(s) with Meckel-Gruber syndrome (PMID: 20232449). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 441 of the TMEM67 protein (p.Arg441Leu). - |
Meckel syndrome, type 3 Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at