chr20-5955109-TAGAA-T

Variant names:

• chr20-5955109-TAGAA-T
• rs762416121
• NM_032485.6:c.351_354delAAAG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_032485.6(MCM8):​c.351_354delAAAG​(p.Lys118GlufsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000559 in 1,592,632 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: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: MCM8 NM_032485.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.28
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286235 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 20-5955109-TAGAA-T is Pathogenic according to our data. Variant chr20-5955109-TAGAA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2172278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	NM_032485.6	MANE Select	c.351_354delAAAG	p.Lys118GlufsTer5	frameshift	Exon 5 of 19	NP_115874.3
	MCM8	NM_001281521.2		c.351_354delAAAG	p.Lys118GlufsTer5	frameshift	Exon 5 of 19	NP_001268450.1	Q9UJA3-4
	MCM8	NM_001281520.2		c.351_354delAAAG	p.Lys118GlufsTer5	frameshift	Exon 5 of 19	NP_001268449.1	Q9UJA3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM8	ENST00000610722.4	TSL:1 MANE Select	c.351_354delAAAG	p.Lys118GlufsTer5	frameshift	Exon 5 of 19	ENSP00000478141.1	Q9UJA3-1
	ENSG00000286235	ENST00000652720.1		c.351_354delAAAG	p.Lys118GlufsTer5	frameshift	Exon 5 of 24	ENSP00000498784.1	A0A494C100
	MCM8	ENST00000378886.6	TSL:1	c.351_354delAAAG	p.Lys118GlufsTer5	frameshift	Exon 5 of 19	ENSP00000368164.2	Q9UJA3-4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152088 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000367 AC: 9 AN: 245372 AF XY: 0.0000453

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000562 AC: 81 AN: 1440544 Hom.: 0 AF XY: 0.0000585 AC XY: 42 AN XY: 717452

African (AFR) AF: 0.0000914 AC: 3 AN: 32834

American (AMR) AF: 0.0000230 AC: 1 AN: 43502

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25792

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 84020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5726

European-Non Finnish (NFE) AF: 0.0000648 AC: 71 AN: 1096170

Other (OTH) AF: 0.0000335 AC: 2 AN: 59616

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152088 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74296

African (AFR) AF: 0.000145 AC: 6 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Premature ovarian failure 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3
Mutation Taster		=0/200	disease causing (fs/PTC)

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: rs762416121; hg19: chr20-5935755;