10-13170915-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018518.5(MCM10):c.8-7C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00872 in 1,608,108 control chromosomes in the GnomAD database, including 303 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (83 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (220 hom.)
• Consequence: MCM10 NM_018518.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004799
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.664

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 10-13170915-C-A is Benign according to our data. Variant chr10-13170915-C-A is described in ClinVar as [Benign]. Clinvar id is 776498.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM10	NM_018518.5	c.8-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000378714.8
MCM10	NM_182751.3	c.8-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
MCM10	XM_011519538.3	c.8-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
MCM10	XM_047425437.1	c.8-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM10	ENST00000378714.8	c.8-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_018518.5	P4
MCM10	ENST00000484800.6	c.8-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A1
MCM10	ENST00000378694.1	c.8-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
MCM10	ENST00000479669.5	c.-233-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2949 AN: 152174 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.0223

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00448

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00852 AC: 2114 AN: 248256 Hom.: 29 AF XY: 0.00770 AC XY: 1036 AN XY: 134614

Gnomad AFR exome AF: 0.0587

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00671

Gnomad SAS exome AF: 0.00899

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00776

GnomAD4 exome AF: 0.00759 AC: 11051 AN: 1455818 Hom.: 220 Cov.: 30 AF XY: 0.00756 AC XY: 5474 AN XY: 723964

Gnomad4 AFR exome AF: 0.0527

Gnomad4 AMR exome AF: 0.00562

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.0520

Gnomad4 SAS exome AF: 0.00888

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00465

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0195 AC: 2964 AN: 152290 Hom.: 83 Cov.: 32 AF XY: 0.0191 AC XY: 1419 AN XY: 74462

Gnomad4 AFR AF: 0.0546

Gnomad4 AMR AF: 0.00746

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.0224

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00448

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00866 Hom.: 9

Bravo AF: 0.0204

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00362

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 10, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	3.9
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00048
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs116353713; hg19: chr10-13212915; COSMIC: COSV66334641;