rs781597825

Variant names:

• chr20-5955177-A-G
• rs781597825
• NM_032485.6:c.412A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-5955177-A-G
• chr20-5955177-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032485.6(MCM8):​c.412A>G​(p.Ile138Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: MCM8 NM_032485.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.796
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042895436).

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.412A>G	p.Ile138Val	missense	Exon 5 of 19	NP_115874.3
	MCM8	NM_001281521.2		c.412A>G	p.Ile138Val	missense	Exon 5 of 19	NP_001268450.1	Q9UJA3-4
	MCM8	NM_001281520.2		c.412A>G	p.Ile138Val	missense	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.412A>G	p.Ile138Val	missense	Exon 5 of 19	ENSP00000478141.1	Q9UJA3-1
	ENSG00000286235	ENST00000652720.1		c.412A>G	p.Ile138Val	missense	Exon 5 of 24	ENSP00000498784.1	A0A494C100
	MCM8	ENST00000378886.6	TSL:1	c.412A>G	p.Ile138Val	missense	Exon 5 of 19	ENSP00000368164.2	Q9UJA3-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152264 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251302 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461614 Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111856

Other (OTH) AF: 0.0000497 AC: 3 AN: 60380

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74390

African (AFR) AF: 0.00 AC: 0 AN: 41478

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68052

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.8
DANN	Benign	0.62
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.80
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.098
Sift	Benign	0.66	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.44		Gain of disorder (P = 0.2121)
MVP		0.12
MPC		0.11
ClinPred		0.032	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.44
Mutation Taster		=89/11	polymorphism

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: rs781597825; hg19: chr20-5935823;