8-47961149-C-T

Variant names:

• chr8-47961149-C-T
• rs749871553
• NM_182746.3:c.5C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_182746.3(MCM4):​c.5C>T​(p.Ser2Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,400,308 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S2W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MCM4 NM_182746.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.95
• Publications: 0 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 4 ACMG points.

• PM1: In a modified_residue N-acetylserine (size 0) in uniprot entity MCM4_HUMAN
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM4	NM_182746.3	MANE Select	c.5C>T	p.Ser2Leu	missense	Exon 2 of 17	NP_877423.1
	MCM4	NM_005914.4		c.5C>T	p.Ser2Leu	missense	Exon 1 of 16	NP_005905.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM4	ENST00000649973.1	MANE Select	c.5C>T	p.Ser2Leu	missense	Exon 2 of 17	ENSP00000496964.1
	MCM4	ENST00000262105.6	TSL:1	c.5C>T	p.Ser2Leu	missense	Exon 1 of 16	ENSP00000262105.2
	MCM4	ENST00000649838.1		c.5C>T	p.Ser2Leu	missense	Exon 2 of 18	ENSP00000497648.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1400308 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695782

African (AFR) AF: 0.0000344 AC: 1 AN: 29034

American (AMR) AF: 0.00 AC: 0 AN: 40186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24734

East Asian (EAS) AF: 0.00 AC: 0 AN: 34008

South Asian (SAS) AF: 0.00 AC: 0 AN: 81348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091414

Other (OTH) AF: 0.00 AC: 0 AN: 58208

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.52
MutPred		0.35		Loss of phosphorylation at S2 (P = 7e-04)
MVP		0.37
MPC		0.16
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		-0.087	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.57
gMVP		0.59
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs749871553; hg19: chr8-48873709;