rs4815879

Variant names:

• chr20-5968888-G-A
• rs4815879
• NM_032485.6:c.1223+863G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032485.6(MCM8):​c.1223+863G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 152,264 control chromosomes in the GnomAD database, including 410 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.068 (410 hom., cov: 32)
• Consequence: MCM8 NM_032485.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.582
• Publications: 5 publications found

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]

MCM8 Gene-Disease associations (from GenCC):

• premature ovarian failure 10

  Inheritance: AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286235 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032485.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	NM_032485.6	MANE Select	c.1223+863G>A		intron	N/A	NP_115874.3
	MCM8	NM_001281521.2		c.1223+863G>A		intron	N/A	NP_001268450.1
	MCM8	NM_001281520.2		c.1223+863G>A		intron	N/A	NP_001268449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	ENST00000610722.4	TSL:1 MANE Select	c.1223+863G>A		intron	N/A	ENSP00000478141.1
	ENSG00000286235	ENST00000652720.1		c.1223+863G>A		intron	N/A	ENSP00000498784.1
	MCM8	ENST00000378886.6	TSL:1	c.1223+863G>A		intron	N/A	ENSP00000368164.2

Frequencies

GnomAD3 genomes AF: 0.0681 AC: 10357 AN: 152146 Hom.: 409 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.0920

Gnomad SAS AF: 0.0768

Gnomad FIN AF: 0.0794

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0961

Gnomad OTH AF: 0.0580

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0680 AC: 10354 AN: 152264 Hom.: 410 Cov.: 32 AF XY: 0.0675 AC XY: 5026 AN XY: 74460

African (AFR) AF: 0.0221 AC: 917 AN: 41558

American (AMR) AF: 0.0560 AC: 856 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 154 AN: 3468

East Asian (EAS) AF: 0.0916 AC: 475 AN: 5186

South Asian (SAS) AF: 0.0764 AC: 369 AN: 4828

European-Finnish (FIN) AF: 0.0794 AC: 842 AN: 10598

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0961 AC: 6533 AN: 68012

Other (OTH) AF: 0.0573 AC: 121 AN: 2110

Alfa AF: 0.0860 Hom.: 2078

Bravo AF: 0.0662

Asia WGS AF: 0.0610 AC: 212 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.5
DANN	Benign	0.53
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4815879; hg19: chr20-5949534;