rs765591205
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_007289.4(MME):c.655-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000825 in 1,576,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_007289.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000417 AC: 10AN: 239716Hom.: 0 AF XY: 0.0000461 AC XY: 6AN XY: 130122
GnomAD4 exome AF: 0.00000843 AC: 12AN: 1424056Hom.: 0 Cov.: 26 AF XY: 0.00000704 AC XY: 5AN XY: 710164
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2T Pathogenic:1
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not provided Pathogenic:1
This sequence change affects an acceptor splice site in intron 7 of the MME gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MME are known to be pathogenic (PMID: 26991897). This variant is present in population databases (rs765591205, gnomAD 0.06%). Disruption of this splice site has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 26991897). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 242841). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at