6-52266620-T-C

Variant names:

• chr6-52266620-T-C
• NM_002388.6:c.2149A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002388.6(MCM3):​c.2149A>G​(p.Met717Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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)
• Consequence: MCM3 NM_002388.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13566694).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002388.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM3	NM_002388.6	MANE Select	c.2149A>G	p.Met717Val	missense	Exon 15 of 17	NP_002379.4
	MCM3	NM_001366369.2		c.2149A>G	p.Met717Val	missense	Exon 15 of 18	NP_001353298.1	A0A0S2Z492
	MCM3	NM_001366370.2		c.2200A>G	p.Met734Val	missense	Exon 15 of 17	NP_001353299.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM3	ENST00000596288.7	TSL:1 MANE Select	c.2149A>G	p.Met717Val	missense	Exon 15 of 17	ENSP00000472940.2	P25205-1
	MCM3	ENST00000616552.4	TSL:1	c.2284A>G	p.Met762Val	missense	Exon 15 of 17	ENSP00000480987.1	P25205-2
	MCM3	ENST00000229854.12	TSL:1	c.2179A>G	p.Met727Val	missense	Exon 14 of 16	ENSP00000229854.6	A0A499FHX9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.17
Sift	Benign	0.51	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.17		Loss of phosphorylation at T722 (P = 0.1226)
MVP		0.60
MPC		0.19
ClinPred		0.61	D
GERP RS		5.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.36
gMVP		0.20
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

hg19: chr6-52131418;