20-5955177-ATA-GTG

Variant names:

• chr20-5955177-ATA-GTG
• NM_032485.6:c.412_414delATAinsGTG
• MCM8 p.Ile138Val

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_032485.6(MCM8):​c.412_414delATAinsGTG​(p.Ile138Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I138M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCM8 NM_032485.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.67
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.412_414delATAinsGTG	p.Ile138Val	missense	N/A	NP_115874.3
	MCM8	NM_001281521.2		c.412_414delATAinsGTG	p.Ile138Val	missense	N/A	NP_001268450.1	Q9UJA3-4
	MCM8	NM_001281520.2		c.412_414delATAinsGTG	p.Ile138Val	missense	N/A	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.412_414delATAinsGTG	p.Ile138Val	missense	N/A	ENSP00000478141.1	Q9UJA3-1
	ENSG00000286235	ENST00000652720.1		c.412_414delATAinsGTG	p.Ile138Val	missense	N/A	ENSP00000498784.1	A0A494C100
	MCM8	ENST00000378886.6	TSL:1	c.412_414delATAinsGTG	p.Ile138Val	missense	N/A	ENSP00000368164.2	Q9UJA3-4

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr20-5935823;