8-47972876-T-G

Variant names:

• chr8-47972876-T-G
• rs762679
• NM_182746.3:c.1948T>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 64 publications found

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]

MCM4 Gene-Disease associations (from GenCC):

• primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

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=0.12584537).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182746.3. 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
	MCM4	NM_182746.3	MANE Select	c.1948T>G	p.Leu650Val	missense	Exon 14 of 17	NP_877423.1
	MCM4	NM_005914.4		c.1948T>G	p.Leu650Val	missense	Exon 13 of 16	NP_005905.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM4	ENST00000649973.1	MANE Select	c.1948T>G	p.Leu650Val	missense	Exon 14 of 17	ENSP00000496964.1
	MCM4	ENST00000262105.6	TSL:1	c.1948T>G	p.Leu650Val	missense	Exon 13 of 16	ENSP00000262105.2
	MCM4	ENST00000649838.1		c.2071T>G	p.Leu691Val	missense	Exon 15 of 18	ENSP00000497648.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.56	N
PhyloP100		7.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.13
Sift	Benign	0.79	T
Sift4G	Benign	0.72	T
Polyphen		0.0050	B
Vest4		0.28
MutPred		0.45		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
Mutation Taster		=98/2	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

dbSNP: rs762679; hg19: chr8-48885436;