rs762679

Positions:

• chr8-47972876-T-A
• chr8-47972876-T-C
• chr8-47972876-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.09

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]

ACMG classification

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/exons	MANE	Protein	UniProt
MCM4	NM_182746.3	c.1948T>A	p.Leu650Met	missense_variant	14/17	ENST00000649973.1	NP_877423.1
MCM4	NM_005914.4	c.1948T>A	p.Leu650Met	missense_variant	13/16		NP_005905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM4	ENST00000649973.1	c.1948T>A	p.Leu650Met	missense_variant	14/17		NM_182746.3	ENSP00000496964	P1

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134338 AN: 152140 Hom.: 59422 Cov.: 33

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

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.: 45 AF XY: 0.860 AC XY: 625052 AN XY: 727120

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.: 33 AF XY: 0.883 AC XY: 65737 AN XY: 74434

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

Submissions by phenotype

Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
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	N
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	T
MutationAssessor	Benign	0.040	.;.;N;.;N;N;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Pathogenic	0.80	T
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	T
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

Other links and lift over

dbSNP: rs762679; hg19: chr8-48885436;