NM_000303.3:c.640-15479C>T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000303.3(PMM2):c.640-15479C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 985,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000303.3 intron
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PMM2 | NM_000303.3 | c.640-15479C>T | intron_variant | Intron 7 of 7 | ENST00000268261.9 | NP_000294.1 | ||
PMM2 | XM_047434215.1 | c.391-15479C>T | intron_variant | Intron 5 of 5 | XP_047290171.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000600 AC: 5AN: 833106Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 384712
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74334
ClinVar
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:7
Variant summary: PMM2 c.640-15479C>T is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5' donor site and one predict the variant strengthens a 5' donor site. Functional studies have shown the variant to result in the creation of a pseudoexon, an additional 123 bp between exon 7 and 8 (Schollen_2007, Vega_2008). The variant was absent in 31398 control chromosomes. c.640-15479C>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (Schollen_2007, Lipinski_2021). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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This sequence change falls in intron 7 of the PMM2 gene. It does not directly change the encoded amino acid sequence of the PMM2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 41 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 17307006, 33643843). 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: 550704). Studies have shown that this variant results in the activation of a cryptic splice site in intron 7 (PMID: 19235233). 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. -
not provided Pathogenic:1
Published functional studies demonstrate a damaging effect on gene splicing causing an in-frame insertion of a pseudoexon (Schollen et al., 2007; Vega et al., 2009); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 19235233, 33643843, 17307006, 19823873, 18571450) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at