NM_018518.5:c.8-7C>A

Variant names:

• chr10-13170915-C-A
• rs116353713
• NM_018518.5:c.8-7C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018518.5(MCM10):​c.8-7C>A variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.0004799
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.664
• Publications: 2 publications found

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]

MCM10 Gene-Disease associations (from GenCC):

• immunodeficiency 80 with or without congenital cardiomyopathy

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 776498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018518.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM10	NM_018518.5	MANE Select	c.8-7C>A		splice_region intron	N/A	NP_060988.3
	MCM10	NM_182751.3		c.8-7C>A		splice_region intron	N/A	NP_877428.1	Q7L590-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM10	ENST00000378714.8	TSL:1 MANE Select	c.8-7C>A		splice_region intron	N/A	ENSP00000367986.3	Q7L590-2
	MCM10	ENST00000484800.6	TSL:1	c.8-7C>A		splice_region intron	N/A	ENSP00000418268.1	Q7L590-1
	MCM10	ENST00000921435.1		c.8-7C>A		splice_region intron	N/A	ENSP00000591494.1

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

GnomAD2 exomes AF: 0.00852 AC: 2114 AN: 248256 AF XY: 0.00770

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 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

African (AFR) AF: 0.0527 AC: 1750 AN: 33228

American (AMR) AF: 0.00562 AC: 248 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 387 AN: 25984

East Asian (EAS) AF: 0.0520 AC: 2059 AN: 39614

South Asian (SAS) AF: 0.00888 AC: 764 AN: 86066

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53358

Middle Eastern (MID) AF: 0.00488 AC: 28 AN: 5740

European-Non Finnish (NFE) AF: 0.00465 AC: 5149 AN: 1107580

Other (OTH) AF: 0.0107 AC: 646 AN: 60098

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

African (AFR) AF: 0.0546 AC: 2269 AN: 41556

American (AMR) AF: 0.00746 AC: 114 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3468

East Asian (EAS) AF: 0.0224 AC: 116 AN: 5188

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4824

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00448 AC: 305 AN: 68030

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00907 Hom.: 10

Bravo AF: 0.0204

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.9
DANN	Benign	0.60
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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