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GeneBe

10-13171148-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_018518.5(MCM10):c.236del(p.Gly79GlufsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,890 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: not found (cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MCM10
NM_018518.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.81
Variant links:
Genes affected
MCM10 (HGNC:18043): (minichromosome maintenance 10 replication initiation factor) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre-RC) and it may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein can interact with MCM2 and MCM6, as well as with the origin recognition protein ORC2. It is regulated by proteolysis and phosphorylation in a cell cycle-dependent manner. Studies of a similar protein in Xenopus suggest that the chromatin binding of this protein at the onset of DNA replication is after pre-RC assembly and before origin unwinding. Alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 10-13171148-TG-T is Pathogenic according to our data. Variant chr10-13171148-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 1077166.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MCM10NM_018518.5 linkuse as main transcriptc.236del p.Gly79GlufsTer6 frameshift_variant 3/20 ENST00000378714.8
MCM10NM_182751.3 linkuse as main transcriptc.236del p.Gly79GlufsTer6 frameshift_variant 3/20
MCM10XM_011519538.3 linkuse as main transcriptc.236del p.Gly79GlufsTer6 frameshift_variant 3/20
MCM10XM_047425437.1 linkuse as main transcriptc.236del p.Gly79GlufsTer6 frameshift_variant 3/20

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MCM10ENST00000378714.8 linkuse as main transcriptc.236del p.Gly79GlufsTer6 frameshift_variant 3/201 NM_018518.5 P4Q7L590-2
MCM10ENST00000484800.6 linkuse as main transcriptc.236del p.Gly79GlufsTer6 frameshift_variant 3/201 A1Q7L590-1
MCM10ENST00000378694.1 linkuse as main transcriptc.236del p.Gly79GlufsTer6 frameshift_variant 2/185
MCM10ENST00000479669.5 linkuse as main transcriptc.-5del 5_prime_UTR_variant 2/34

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461890
Hom.:
0
Cov.:
32
AF XY:
0.0000193
AC XY:
14
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000225
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
33
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Immunodeficiency 80 with or without congenital cardiomyopathy Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 11, 2021- -
Fetal Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingOxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation TrustMar 23, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-13213148; API