8-47960493-CG-C

Position:

• chr8-47960493-CG-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000518221.5(MCM4):​c.-15+179del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 152,172 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0039 (4 hom., cov: 32)
• Consequence: MCM4 ENST00000518221.5 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.466

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00393 (598/152172) while in subpopulation SAS AF= 0.0241 (116/4814). AF 95% confidence interval is 0.0205. There are 4 homozygotes in gnomad4. There are 304 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM4	ENST00000518221.5	c.-15+179del		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 594 AN: 152054 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00669

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00393 AC: 598 AN: 152172 Hom.: 4 Cov.: 32 AF XY: 0.00409 AC XY: 304 AN XY: 74396

Gnomad4 AFR AF: 0.00482

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0241

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.000380 Hom.: 0

Bravo AF: 0.00353

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs376290735; hg19: chr8-48873053;