20-5955179-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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 criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.503

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]

ACMG classification

Verdict is Benign. Variant got -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]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM8	NM_032485.6	c.414A>G	p.Ile138Met	missense_variant	5/19	ENST00000610722.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM8	ENST00000610722.4	c.414A>G	p.Ile138Met	missense_variant	5/19	1	NM_032485.6	P1

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

GnomAD3 exomes AF: 0.00620 AC: 1559 AN: 251278 Hom.: 27 AF XY: 0.00790 AC XY: 1073 AN XY: 135800

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 SAS exome AF: 0.0293

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

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0278

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00229

Gnomad4 OTH exome AF: 0.00512

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

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0248

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00384

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00417 Hom.: 10

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MCM8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.71	T;T;T;.;T
MetaRNN	Benign	0.0060	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.29	N;N;N;.;N
REVEL	Benign	0.057
Sift	Benign	0.13	T;T;T;.;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.015	B;B;.;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs145133959; hg19: chr20-5935825; COSMIC: COSV99177536; COSMIC: COSV99177536;