rs386834183
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_153704.6(TMEM67):c.1322G>A(p.Arg441His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM67 | NM_153704.6 | c.1322G>A | p.Arg441His | missense_variant | 13/28 | ENST00000453321.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM67 | ENST00000453321.8 | c.1322G>A | p.Arg441His | missense_variant | 13/28 | 1 | NM_153704.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152038Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251258Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135806
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461714Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727146
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152038Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74260
ClinVar
Submissions by phenotype
Meckel syndrome, type 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Mar 05, 2020 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 441 of the TMEM67 protein (p.Arg441His). 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. 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: 972688). This variant has not been reported in the literature in individuals affected with TMEM67-related conditions. This variant is present in population databases (rs386834183, gnomAD 0.003%). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at