Variant 6-52267947-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The ENST00000596288.7(MCM3):c.1990C>A(p.Arg664Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MCM3
ENST00000596288.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73

Variant links:

Genes affected

MCM3 (HGNC:6945): (minichromosome maintenance complex component 3) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein is a subunit of the protein complex that consists of MCM2-7. It has been shown to interact directly with MCM5/CDC46. This protein also interacts with and is acetylated by MCM3AP, a chromatin-associated acetyltransferase. The acetylation of this protein inhibits the initiation of DNA replication and cell cycle progression. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2018]

MCM3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity MCM3_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18879104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM3	NM_002388.6 linkuse as main transcript	c.1990C>A	p.Arg664Ser	missense_variant	14/17	ENST00000596288.7	NP_002379.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM3	ENST00000596288.7 linkuse as main transcript	c.1990C>A	p.Arg664Ser	missense_variant	14/17	1	NM_002388.6	ENSP00000472940	P1	P25205-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458922

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725976

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The c.1990C>A (p.R664S) alteration is located in exon 14 (coding exon 14) of the MCM3 gene. This alteration results from a C to A substitution at nucleotide position 1990, causing the arginine (R) at amino acid position 664 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.;T;.

Eigen

Benign

0.068

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

D;.;D;D;D

M_CAP

Benign

0.0054

MetaRNN

Benign

0.19

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.8

N;.;.;.;D

REVEL

Benign

0.074

Sift

Benign

0.058

T;.;.;.;T

Sift4G

Benign

0.13

T;T;T;T;D

Polyphen

0.013

B;.;.;.;.

Vest4

0.46

MutPred

0.33

Gain of phosphorylation at R664 (P = 4e-04);.;.;.;.;

MVP

0.60

MPC

0.24

ClinPred

0.79

GERP RS

4.6

Varity_R

0.18

gMVP

0.38

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over