8-47960773-G-T

Variant names:

• chr8-47960773-G-T
• rs17334298
• ENST00000518221.5:c.-14-358G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000518221.5(MCM4):​c.-14-358G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MCM4 ENST00000518221.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0230
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000518221.5. 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.-256G>T		upstream_gene	N/A	NP_877423.1	P33991
	MCM4	NM_005914.4		c.-372G>T		upstream_gene	N/A	NP_005905.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM4	ENST00000518221.5	TSL:4	c.-14-358G>T		intron	N/A	ENSP00000430329.1	E5RFR3
	MCM4	ENST00000649973.1	MANE Select	c.-256G>T		upstream_gene	N/A	ENSP00000496964.1	P33991
	MCM4	ENST00000262105.6	TSL:1	c.-372G>T		upstream_gene	N/A	ENSP00000262105.2	P33991

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 89780 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 47566

African (AFR) AF: 0.00 AC: 0 AN: 1654

American (AMR) AF: 0.00 AC: 0 AN: 1082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2708

East Asian (EAS) AF: 0.00 AC: 0 AN: 3296

South Asian (SAS) AF: 0.00 AC: 0 AN: 13670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 358

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 55556

Other (OTH) AF: 0.00 AC: 0 AN: 5292

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.4
DANN	Benign	0.68
PhyloP100		0.023
PromoterAI		-0.38	Neutral

Splicing

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

Other links and lift over

dbSNP: rs17334298; hg19: chr8-48873333;