rs372051998
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000530.8(MPZ):āc.542A>Gā(p.Tyr181Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,014 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 Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. Y181Y) has been classified as Likely benign.
Frequency
Consequence
NM_000530.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MPZ | NM_000530.8 | c.542A>G | p.Tyr181Cys | missense_variant | 4/6 | ENST00000533357.5 | NP_000521.2 | |
MPZ | NM_001315491.2 | c.542A>G | p.Tyr181Cys | missense_variant | 4/6 | NP_001302420.1 | ||
MPZ | XM_017001321.3 | c.572A>G | p.Tyr191Cys | missense_variant | 4/6 | XP_016856810.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MPZ | ENST00000533357.5 | c.542A>G | p.Tyr181Cys | missense_variant | 4/6 | 1 | NM_000530.8 | ENSP00000432943.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152014Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152014Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74240
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2023 | Reported as a paternally inherited variant in a family with neuropathy in published literature (Kushlaf et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20461396, 26310628, Kushlaf2019[casereport]) - |
Charcot-Marie-Tooth disease, type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 08, 2018 | This sequence change replaces tyrosine with cysteine at codon 181 of the MPZ protein (p.Tyr181Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MPZ-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at