chr20-5955179-A-G

Variant names:

• chr20-5955179-A-G
• rs145133959
• NM_032485.6:c.414A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032485.6(MCM8):​c.414A>G​(p.Ile138Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,613,946 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I138V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (80 hom.)
• Consequence: MCM8 NM_032485.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.503
• Publications: 16 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: AD, AR 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059596).
• BP6: Variant 20-5955179-A-G is Benign according to our data. Variant chr20-5955179-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 775586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00319 (486/152362) while in subpopulation SAS AF = 0.0248 (120/4830). AF 95% confidence interval is 0.0212. There are 4 homozygotes in GnomAd4. There are 253 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.414A>G	p.Ile138Met	missense	Exon 5 of 19	NP_115874.3
	MCM8	NM_001281521.2		c.414A>G	p.Ile138Met	missense	Exon 5 of 19	NP_001268450.1	Q9UJA3-4
	MCM8	NM_001281520.2		c.414A>G	p.Ile138Met	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.414A>G	p.Ile138Met	missense	Exon 5 of 19	ENSP00000478141.1	Q9UJA3-1
	ENSG00000286235	ENST00000652720.1		c.414A>G	p.Ile138Met	missense	Exon 5 of 24	ENSP00000498784.1	A0A494C100
	MCM8	ENST00000378886.6	TSL:1	c.414A>G	p.Ile138Met	missense	Exon 5 of 19	ENSP00000368164.2	Q9UJA3-4

Frequencies

GnomAD3 genomes AF: 0.00322 AC: 490 AN: 152244 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00620 AC: 1559 AN: 251278 AF XY: 0.00790

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00395 AC: 5766 AN: 1461584 Hom.: 80 Cov.: 30 AF XY: 0.00481 AC XY: 3500 AN XY: 727092

African (AFR) AF: 0.000358 AC: 12 AN: 33474

American (AMR) AF: 0.00125 AC: 56 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 292 AN: 26126

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39664

South Asian (SAS) AF: 0.0278 AC: 2400 AN: 86182

European-Finnish (FIN) AF: 0.00110 AC: 59 AN: 53414

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5764

European-Non Finnish (NFE) AF: 0.00229 AC: 2551 AN: 1111870

Other (OTH) AF: 0.00512 AC: 309 AN: 60374

GnomAD4 genome AF: 0.00319 AC: 486 AN: 152362 Hom.: 4 Cov.: 33 AF XY: 0.00340 AC XY: 253 AN XY: 74508

African (AFR) AF: 0.000409 AC: 17 AN: 41584

American (AMR) AF: 0.00131 AC: 20 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0248 AC: 120 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.00384 AC: 261 AN: 68038

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00402 Hom.: 11

Bravo AF: 0.00255

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00669 AC: 812

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00575

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	MCM8-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.68
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.50
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.057
Sift	Benign	0.13	T
Sift4G	Benign	0.23	T
Polyphen		0.015	B
Vest4		0.28
MVP		0.22
MPC		0.14
ClinPred		0.0072	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.48
Mutation Taster		=100/0	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: rs145133959; hg19: chr20-5935825; COSMIC: COSV99177536; COSMIC: COSV99177536;