20-5955186-A-G

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.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
• 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=0.0047038198).
• 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_single_submitter, 1 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 GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM8	NM_032485.6	c.421A>G	p.Ile141Val	missense_variant	5/19	ENST00000610722.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM8	ENST00000610722.4	c.421A>G	p.Ile141Val	missense_variant	5/19	1	NM_032485.6	P1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152238 Hom.: 1 Cov.: 33

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.: 3 AF XY: 0.00250 AC XY: 340 AN XY: 135806

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.: 15 Cov.: 31 AF XY: 0.00151 AC XY: 1100 AN XY: 727108

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.: 1 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74506

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.: 1

Bravo AF: 0.00110

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00211 AC: 256

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.00186

EpiControl AF: 0.000948

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	0.064
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	11
Dann	Benign	0.87
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.72	T;T;T;.;T
MetaRNN	Benign	0.0047	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;L;L;L
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs116926921; hg19: chr20-5935832;