8-47972876-T-G

Position:

• chr8-47972876-T-G

Variant summary

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

The NM_182746.3(MCM4):​c.1948T>G​(p.Leu650Val) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L650M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCM4 NM_182746.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 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=0.12584537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM4	NM_182746.3	c.1948T>G	p.Leu650Val	missense_variant	14/17	ENST00000649973.1	NP_877423.1
MCM4	NM_005914.4	c.1948T>G	p.Leu650Val	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>G	p.Leu650Val	missense_variant	14/17		NM_182746.3	ENSP00000496964.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Benign	0.23
DEOGEN2	Benign	0.072	.;.;T;.;T;T;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;.;D;.;D;D;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.56	.;.;N;.;N;N;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.14	.;.;N;.;N;.;.;.
REVEL	Benign	0.13
Sift	Benign	0.79	.;.;T;.;T;.;.;.
Sift4G	Benign	0.72	.;.;T;.;T;.;.;.
Polyphen		0.0050	.;.;B;.;B;B;.;.
Vest4		0.28, 0.32
MutPred		0.45		Gain of loop (P = 0.0097);.;Gain of loop (P = 0.0097);.;Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);.;.;
MVP		0.11
MPC		0.19
ClinPred		0.55	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
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;