6-52267932-C-T

Variant names:

• chr6-52267932-C-T
• NM_002388.6:c.2005G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002388.6(MCM3):​c.2005G>A​(p.Glu669Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MCM3 NM_002388.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15248835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM3	NM_002388.6	c.2005G>A	p.Glu669Lys	missense_variant	Exon 14 of 17	ENST00000596288.7	NP_002379.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM3	ENST00000596288.7	c.2005G>A	p.Glu669Lys	missense_variant	Exon 14 of 17	1	NM_002388.6	ENSP00000472940.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1432102 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 714428

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2005G>A (p.E669K) alteration is located in exon 14 (coding exon 14) of the MCM3 gene. This alteration results from a G to A substitution at nucleotide position 2005, causing the glutamic acid (E) at amino acid position 669 to be replaced by a lysine (K). 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	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;.;.;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.93	D;.;D;D;D
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.83	N;.;.;.;N
REVEL	Benign	0.11
Sift	Benign	0.44	T;.;.;.;T
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.
Vest4		0.31
MutPred		0.42		Gain of MoRF binding (P = 0.0229);.;.;.;.;
MVP		0.44
MPC		0.22
ClinPred		0.50	T
GERP RS		4.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.15
gMVP		0.24

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.

Other links and lift over

hg19: chr6-52132730;