20-5957187-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_032485.6(MCM8):c.548A>G(p.Asn183Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 1,613,648 control chromosomes in the GnomAD database, including 261 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.024 (133 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (128 hom.)
• Consequence: MCM8 NM_032485.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.105

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014059246).
• BP6: Variant 20-5957187-A-G is Benign according to our data. Variant chr20-5957187-A-G is described in ClinVar as [Benign]. Clinvar id is 783858.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM8	NM_032485.6	c.548A>G	p.Asn183Ser	missense_variant	6/19	ENST00000610722.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM8	ENST00000610722.4	c.548A>G	p.Asn183Ser	missense_variant	6/19	1	NM_032485.6	P1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3671 AN: 152202 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.0770

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00771

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00863 AC: 2168 AN: 251182 Hom.: 49 AF XY: 0.00727 AC XY: 987 AN XY: 135764

Gnomad AFR exome AF: 0.0790

Gnomad AMR exome AF: 0.00698

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.00701

Gnomad SAS exome AF: 0.00579

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.00752

GnomAD4 exome AF: 0.00403 AC: 5890 AN: 1461328 Hom.: 128 Cov.: 30 AF XY: 0.00388 AC XY: 2819 AN XY: 726990

Gnomad4 AFR exome AF: 0.0784

Gnomad4 AMR exome AF: 0.00779

Gnomad4 ASJ exome AF: 0.00605

Gnomad4 EAS exome AF: 0.00716

Gnomad4 SAS exome AF: 0.00648

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.00924

GnomAD4 genome AF: 0.0242 AC: 3682 AN: 152320 Hom.: 133 Cov.: 32 AF XY: 0.0236 AC XY: 1759 AN XY: 74482

Gnomad4 AFR AF: 0.0770

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00792

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.00573 Hom.: 22

Bravo AF: 0.0268

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0749 AC: 330

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00967 AC: 1174

Asia WGS AF: 0.0200 AC: 69 AN: 3474

EpiCase AF: 0.00300

EpiControl AF: 0.00184

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	4.2
Dann	Benign	0.83
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.031	T;T;T;.;T
MetaRNN	Benign	0.0014	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.020	N;N;N;.;N
REVEL	Benign	0.072
Sift	Benign	0.83	T;T;T;.;T
Sift4G	Benign	0.75	T;T;T;T;T
Polyphen		0.0	B;B;.;B;B
Vest4		0.044
MVP		0.19
MPC		0.10
ClinPred		0.00069	T
GERP RS		3.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.015
gMVP		0.24

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: rs16991591; hg19: chr20-5937833;