rs762679

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182746.3(MCM4):c.1948T>A(p.Leu650Met) variant causes a missense change. The variant allele was found at a frequency of 0.862 in 1,613,868 control chromosomes in the GnomAD database, including 600,719 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 59487 hom., cov: 33)

Exomes 𝑓: 0.86 ( 541232 hom. )

Consequence

MCM4
NM_182746.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.09

Variant links:

Genes affected

MCM4 (HGNC:6947): (minichromosome maintenance complex component 4) 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 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. The MCM complex consisting of this protein and MCM2, 6 and 7 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The phosphorylation of this protein by CDC2 kinase reduces the DNA helicase activity and chromatin binding of the MCM complex. This gene is mapped to a region on the chromosome 8 head-to-head next to the PRKDC/DNA-PK, a DNA-activated protein kinase involved in the repair of DNA double-strand breaks. Alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

MCM4 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=5.45541E-7).

BP6

Variant 8-47972876-T-A is Benign according to our data. Variant chr8-47972876-T-A is described in ClinVar as [Benign]. Clinvar id is 363238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-47972876-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM4	NM_182746.3 link	c.1948T>A	p.Leu650Met	missense_variant	Exon 14 of 17	ENST00000649973.1	NP_877423.1	P33991B3KMX0
MCM4	NM_005914.4 link	c.1948T>A	p.Leu650Met	missense_variant	Exon 13 of 16		NP_005905.2	P33991B4DLA6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM4	ENST00000649973.1 link	c.1948T>A	p.Leu650Met	missense_variant	Exon 14 of 17		NM_182746.3	ENSP00000496964.1		P33991

Frequencies

GnomAD3 genomes

AF:

0.883

AC:

134338

AN:

152140

Hom.:

59422

Cov.:

show subpopulations

Gnomad AFR

AF:

0.925

Gnomad AMI

AF:

0.930

Gnomad AMR

AF:

0.911

Gnomad ASJ

AF:

0.844

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.868

Gnomad FIN

AF:

0.838

Gnomad MID

AF:

0.816

Gnomad NFE

AF:

0.851

Gnomad OTH

AF:

0.889

GnomAD3 exomes

AF:

0.872

AC:

219014

AN:

251290

Hom.:

95914

AF XY:

0.867

AC XY:

117747

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.926

Gnomad AMR exome

AF:

0.928

Gnomad ASJ exome

AF:

0.827

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.850

Gnomad FIN exome

AF:

0.835

Gnomad NFE exome

AF:

0.843

Gnomad OTH exome

AF:

0.855

GnomAD4 exome

AF:

0.860

AC:

1256733

AN:

1461610

Hom.:

541232

Cov.:

AF XY:

0.860

AC XY:

625052

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.926

Gnomad4 AMR exome

AF:

0.925

Gnomad4 ASJ exome

AF:

0.822

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.854

Gnomad4 FIN exome

AF:

0.836

Gnomad4 NFE exome

AF:

0.852

Gnomad4 OTH exome

AF:

0.868

GnomAD4 genome

AF:

0.883

AC:

134465

AN:

152258

Hom.:

59487

Cov.:

AF XY:

0.883

AC XY:

65737

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.926

Gnomad4 AMR

AF:

0.911

Gnomad4 ASJ

AF:

0.844

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.868

Gnomad4 FIN

AF:

0.838

Gnomad4 NFE

AF:

0.851

Gnomad4 OTH

AF:

0.890

Alfa

AF:

0.860

Hom.:

42497

Bravo

AF:

0.891

TwinsUK

AF:

0.843

AC:

3127

ALSPAC

AF:

0.854

AC:

3291

ESP6500AA

AF:

0.924

AC:

4069

ESP6500EA

AF:

0.847

AC:

7285

ExAC

AF:

0.867

AC:

105227

Asia WGS

AF:

0.929

AC:

3232

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency

Benign:3

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

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

0.048

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.37

DEOGEN2

Benign

0.092

.;.;T;.;T;T;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.48

T;T;.;T;.;T;T;T

MetaRNN

Benign

5.5e-7

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.040

.;.;N;.;N;N;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.95

.;.;N;.;N;.;.;.

REVEL

Benign

0.090

Sift

Benign

1.0

.;.;T;.;T;.;.;.

Sift4G

Benign

1.0

.;.;T;.;T;.;.;.

Polyphen

0.0020

.;.;B;.;B;B;.;.

Vest4

0.12, 0.17

MPC

0.18

ClinPred

0.0071

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.29

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