8-47960892-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000518221.5(MCM4):c.-14-239C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 456,664 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.022 (60 hom., cov: 33)
  • Exomes 𝑓: 0.028 (145 hom.)
• Consequence: MCM4 ENST00000518221.5 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.35

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0218 (3319/152346) while in subpopulation NFE AF= 0.0351 (2386/68016). AF 95% confidence interval is 0.0339. There are 60 homozygotes in gnomad4. There are 1493 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM4	NM_182746.3			upstream_gene_variant		ENST00000649973.1
MCM4	NM_005914.4			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM4	ENST00000649973.1			upstream_gene_variant			NM_182746.3	P1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3319 AN: 152228 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.00518

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.0280 AC: 8510 AN: 304318 Hom.: 145 Cov.: 3 AF XY: 0.0275 AC XY: 4400 AN XY: 160218

Gnomad4 AFR exome AF: 0.00594

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.0240

Gnomad4 NFE exome AF: 0.0343

Gnomad4 OTH exome AF: 0.0249

GnomAD4 genome AF: 0.0218 AC: 3319 AN: 152346 Hom.: 60 Cov.: 33 AF XY: 0.0200 AC XY: 1493 AN XY: 74504

Gnomad4 AFR AF: 0.00517

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.0204

Gnomad4 NFE AF: 0.0351

Gnomad4 OTH AF: 0.0217

Alfa AF: 0.0232 Hom.: 4

Bravo AF: 0.0205

Asia WGS AF: 0.00866 AC: 30 AN: 3478

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	2.4
Dann	Benign	0.92

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17334305; hg19: chr8-48873452;