NM_032485.6:c.421A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032485.6(MCM8):c.421A>G(p.Ile141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,964 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 15 hom. )

Consequence

MCM8
NM_032485.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.105

Variant links:

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 links:

ENSG00000286235 (HGNC:):

ENSG00000286235 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047038198).

BP6

Variant 20-5955186-A-G is Benign according to our data. Variant chr20-5955186-A-G is described in ClinVar as [Benign]. Clinvar id is 708742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00128 (195/152356) while in subpopulation EAS AF= 0.00791 (41/5186). AF 95% confidence interval is 0.00599. There are 1 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM8	NM_032485.6 link	c.421A>G	p.Ile141Val	missense_variant	Exon 5 of 19	ENST00000610722.4	NP_115874.3	Q9UJA3-1B4DN82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM8	ENST00000610722.4 link	c.421A>G	p.Ile141Val	missense_variant	Exon 5 of 19	1	NM_032485.6	ENSP00000478141.1		Q9UJA3-1
ENSG00000286235	ENST00000652720.1 link	c.421A>G	p.Ile141Val	missense_variant	Exon 5 of 24			ENSP00000498784.1		A0A494C100

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00770

Gnomad SAS

AF:

0.00703

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000852

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00220

AC:

553

AN:

251286

Hom.:

AF XY:

0.00250

AC XY:

340

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00586

Gnomad EAS exome

AF:

0.00701

Gnomad SAS exome

AF:

0.00553

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00139

AC:

2025

AN:

1461608

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1100

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.00528

Gnomad4 EAS exome

AF:

0.00716

Gnomad4 SAS exome

AF:

0.00622

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000741

Gnomad4 OTH exome

AF:

0.00260

GnomAD4 genome

AF:

0.00128

AC:

195

AN:

152356

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00791

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000867

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00158

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00211

AC:

256

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.00186

EpiControl

AF:

0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.042

.;T;.;T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.72

T;T;T;.;T

MetaRNN

Benign

0.0047

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;L;L;L;L

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.77

N;N;N;.;N

REVEL

Benign

0.036

Sift

Benign

0.17

T;T;T;.;T

Sift4G

Uncertain

0.057

T;T;T;T;T

Polyphen

0.0

B;B;.;B;B

Vest4

0.16

MVP

0.15

MPC

0.11

ClinPred

0.0020

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.037

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over