rs777604559
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002437.5(MPV17):βc.135delβ(p.Glu45AspfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. E45E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002437.5 frameshift
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 |
---|---|---|---|---|---|---|---|
MPV17 | NM_002437.5 | c.135del | p.Glu45AspfsTer8 | frameshift_variant | 3/8 | ENST00000380044.6 | |
MPV17 | XM_005264326.5 | c.135del | p.Glu45AspfsTer8 | frameshift_variant | 3/8 | ||
MPV17 | XM_017004151.2 | c.87del | p.Glu29AspfsTer8 | frameshift_variant | 3/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPV17 | ENST00000380044.6 | c.135del | p.Glu45AspfsTer8 | frameshift_variant | 3/8 | 1 | NM_002437.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251448Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727240
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2014 | c.135delA: p.Glu45AspfsX8 (E45DfsX8) in exon 3 of the MPV17 gene (NM_002437.4). The normal sequence with the base that is deleted in braces is: AGGA{A}CACC. The c.135delA mutation in the MPV17 gene has been reported previously in association with mitochondrial DNA depletion syndrome (Uusimaa et al., 2014). The deletion causes a frameshift starting with codon Glutamic Acid 45, changes this amino acid to an Aspartic Acid residue and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Glu45AspfsX8. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in MITONUC-MITOP panel(s). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Glu45Aspfs*8) in the MPV17 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPV17 are known to be pathogenic (PMID: 23714749). This variant is present in population databases (rs777604559, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 23714749). ClinVar contains an entry for this variant (Variation ID: 214662). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 26, 2017 | - - |
Charcot-Marie-Tooth disease, axonal, type 2EE Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at