chr10-13175686-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_018518.5(MCM10):c.764+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.0000593 in 1,585,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000065 ( 0 hom. )
Consequence
MCM10
NM_018518.5 splice_donor_5th_base, intron
NM_018518.5 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9979
2
Clinical Significance
Conservation
PhyloP100: 4.36
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 10-13175686-G-A is Pathogenic according to our data. Variant chr10-13175686-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1077167.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCM10 | NM_018518.5 | c.764+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000378714.8 | |||
MCM10 | NM_182751.3 | c.767+5G>A | splice_donor_5th_base_variant, intron_variant | ||||
MCM10 | XM_011519538.3 | c.767+5G>A | splice_donor_5th_base_variant, intron_variant | ||||
MCM10 | XM_047425437.1 | c.764+5G>A | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCM10 | ENST00000378714.8 | c.764+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_018518.5 | P4 | |||
MCM10 | ENST00000484800.6 | c.767+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | A1 | ||||
MCM10 | ENST00000378694.1 | c.764+5G>A | splice_donor_5th_base_variant, intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000430 AC: 1AN: 232426Hom.: 0 AF XY: 0.00000796 AC XY: 1AN XY: 125660
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GnomAD4 exome AF: 0.0000649 AC: 93AN: 1433728Hom.: 0 Cov.: 28 AF XY: 0.0000548 AC XY: 39AN XY: 711650
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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 provided | literature only | OMIM | May 11, 2021 | - - |
Fetal Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust | Mar 23, 2023 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at