20-5955229-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032485.6(MCM8):c.464G>A(p.Cys155Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00313 in 1,612,980 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (43 hom.)
• Consequence: MCM8 NM_032485.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.54

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=0.009202808).
• BP6: Variant 20-5955229-G-A is Benign according to our data. Variant chr20-5955229-G-A is described in ClinVar as [Benign]. Clinvar id is 714894.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1646/152318) while in subpopulation AFR AF= 0.033 (1371/41564). AF 95% confidence interval is 0.0315. There are 26 homozygotes in gnomad4. There are 793 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM8	NM_032485.6	c.464G>A	p.Cys155Tyr	missense_variant	5/19	ENST00000610722.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM8	ENST00000610722.4	c.464G>A	p.Cys155Tyr	missense_variant	5/19	1	NM_032485.6	P1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1641 AN: 152200 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00769

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00481 AC: 1202 AN: 249980 Hom.: 12 AF XY: 0.00434 AC XY: 586 AN XY: 135016

Gnomad AFR exome AF: 0.0367

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.00577

Gnomad EAS exome AF: 0.00703

Gnomad SAS exome AF: 0.00547

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00233 AC: 3401 AN: 1460662 Hom.: 43 Cov.: 31 AF XY: 0.00233 AC XY: 1691 AN XY: 726510

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.00236

Gnomad4 ASJ exome AF: 0.00521

Gnomad4 EAS exome AF: 0.00714

Gnomad4 SAS exome AF: 0.00631

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000780

Gnomad4 OTH exome AF: 0.00482

GnomAD4 genome AF: 0.0108 AC: 1646 AN: 152318 Hom.: 26 Cov.: 33 AF XY: 0.0106 AC XY: 793 AN XY: 74486

Gnomad4 AFR AF: 0.0330

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00790

Gnomad4 SAS AF: 0.00705

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00303 Hom.: 5

Bravo AF: 0.0117

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00526 AC: 639

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00101

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	Pathogenic	0.71
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T;T;T;.;T
MetaRNN	Benign	0.0092	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-8.6	D;D;D;.;D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;.;D;P
Vest4		0.59
MVP		0.75
MPC		0.31
ClinPred		0.067	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.87

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: rs58487183; hg19: chr20-5935875;