rs886062973

Variant names:

• chr8-47961081-G-A
• rs886062973
• ENST00000262105.6:c.-64G>A

Variant summary

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

The NM_005914.4(MCM4):​c.-64G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00036 in 1,485,282 control chromosomes in the GnomAD database, including 1 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: 0.00037 (1 hom.)
• Consequence: MCM4 NM_005914.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.749
• 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005914.4. 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.-14-50G>A		intron	N/A	NP_877423.1	P33991
	MCM4	NM_005914.4		c.-64G>A		5_prime_UTR	Exon 1 of 16	NP_005905.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM4	ENST00000262105.6	TSL:1	c.-64G>A		5_prime_UTR	Exon 1 of 16	ENSP00000262105.2	P33991
	MCM4	ENST00000649973.1	MANE Select	c.-14-50G>A		intron	N/A	ENSP00000496964.1	P33991
	MCM4	ENST00000936720.1		c.-64G>A		5_prime_UTR	Exon 1 of 17	ENSP00000606779.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000371 AC: 495 AN: 1333076 Hom.: 1 Cov.: 27 AF XY: 0.000376 AC XY: 248 AN XY: 659494

African (AFR) AF: 0.0000739 AC: 2 AN: 27080

American (AMR) AF: 0.000186 AC: 6 AN: 32246

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 30 AN: 23632

East Asian (EAS) AF: 0.0000335 AC: 1 AN: 29854

South Asian (SAS) AF: 0.00 AC: 0 AN: 76052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33480

Middle Eastern (MID) AF: 0.00419 AC: 22 AN: 5252

European-Non Finnish (NFE) AF: 0.000386 AC: 405 AN: 1050032

Other (OTH) AF: 0.000523 AC: 29 AN: 55448

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41468

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68022

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000325

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	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	-0.71
CADD	Benign	5.2
DANN	Benign	0.83
PhyloP100		-0.75
PromoterAI		-0.0070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 50

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886062973; hg19: chr8-48873641;