rs559247482

Variant names:

• chr8-47960955-C-T
• rs559247482
• NM_182746.3:c.-74C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_182746.3(MCM4):​c.-74C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000687 in 566,592 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (7 hom.)
• Consequence: MCM4 NM_182746.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.67
• 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, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

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.-74C>T		5_prime_UTR	Exon 1 of 17	NP_877423.1	P33991
	MCM4	NM_005914.4		c.-190C>T		5_prime_UTR	Exon 1 of 16	NP_005905.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM4	ENST00000649973.1	MANE Select	c.-74C>T		5_prime_UTR	Exon 1 of 17	ENSP00000496964.1	P33991
	MCM4	ENST00000262105.6	TSL:1	c.-190C>T		5_prime_UTR	Exon 1 of 16	ENSP00000262105.2	P33991
	MCM4	ENST00000649838.1		c.-74C>T		5_prime_UTR	Exon 1 of 18	ENSP00000497648.1	A0A3B3IT92

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00723

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000845 AC: 350 AN: 414262 Hom.: 7 Cov.: 6 AF XY: 0.00132 AC XY: 284 AN XY: 215934

African (AFR) AF: 0.00 AC: 0 AN: 8352

American (AMR) AF: 0.000135 AC: 1 AN: 7410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11188

East Asian (EAS) AF: 0.00 AC: 0 AN: 22560

South Asian (SAS) AF: 0.00930 AC: 315 AN: 33884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27880

Middle Eastern (MID) AF: 0.00225 AC: 4 AN: 1776

European-Non Finnish (NFE) AF: 0.0000791 AC: 22 AN: 278224

Other (OTH) AF: 0.000348 AC: 8 AN: 22988

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74504

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00703 AC: 34 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000907

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.8
DANN	Benign	0.89
PhyloP100		-1.7
PromoterAI		-0.031	Neutral
Mutation Taster		=299/1	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: rs559247482; hg19: chr8-48873515;