20-5955109-TAGAA-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_032485.6(MCM8):c.351_354del(p.Lys118GlufsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000559 in 1,592,632 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000056 ( 0 hom. )
Consequence
MCM8
NM_032485.6 frameshift
NM_032485.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.28
Genes affected
MCM8 (HGNC:16147): (minichromosome maintenance 8 homologous recombination repair factor) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the mini-chromosome maintenance proteins is a key component of the pre-replication complex and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein contains the central domain that is conserved among the mini-chromosome maintenance proteins. The encoded protein may interact with other mini-chromosome maintenance proteins and play a role in DNA replication. This gene may be associated with length of reproductive lifespan and menopause. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-5955109-TAGAA-T is Pathogenic according to our data. Variant chr20-5955109-TAGAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 2172278.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCM8 | NM_032485.6 | c.351_354del | p.Lys118GlufsTer5 | frameshift_variant | 5/19 | ENST00000610722.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCM8 | ENST00000610722.4 | c.351_354del | p.Lys118GlufsTer5 | frameshift_variant | 5/19 | 1 | NM_032485.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152088Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000367 AC: 9AN: 245372Hom.: 0 AF XY: 0.0000453 AC XY: 6AN XY: 132464
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GnomAD4 exome AF: 0.0000562 AC: 81AN: 1440544Hom.: 0 AF XY: 0.0000585 AC XY: 42AN XY: 717452
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2022 | This sequence change creates a premature translational stop signal (p.Lys118Glufs*5) in the MCM8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MCM8 are known to be pathogenic (PMID: 22771120, 25873734, 31042289). This variant is present in population databases (rs762416121, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with premature ovarian insufficiency (PMID: 32048466). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at