6-52269225-G-A

Position:

• chr6-52269225-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002388.6(MCM3):​c.1829C>T​(p.Thr610Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCM3 NM_002388.6 missense, splice_region
• Scores: Splicing: ADA: 0.3841
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.35

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM3	NM_002388.6	c.1829C>T	p.Thr610Ile	missense_variant, splice_region_variant	13/17	ENST00000596288.7	NP_002379.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM3	ENST00000596288.7	c.1829C>T	p.Thr610Ile	missense_variant, splice_region_variant	13/17	1	NM_002388.6	ENSP00000472940.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.1829C>T (p.T610I) alteration is located in exon 13 (coding exon 13) of the MCM3 gene. This alteration results from a C to T substitution at nucleotide position 1829, causing the threonine (T) at amino acid position 610 to be replaced by an isoleucine (I). 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	0.94
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.6	D;.;.;.;D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;.;.;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.82
MutPred		0.55		Loss of phosphorylation at T610 (P = 0.0168);.;.;.;.;
MVP		0.83
MPC		0.65
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.93
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.38
dbscSNV1_RF	Benign	0.59
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: chr6-52134023;