chr8-47960940-C-T

Variant names:

• chr8-47960940-C-T
• rs17287526
• ENST00000262105.6:c.-205C>T

Variant summary

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

The ENST00000262105.6(MCM4):​c.-205C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 520,976 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (7 hom.)
• Consequence: MCM4 ENST00000262105.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.18
• Publications: 1 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 GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262105.6. 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.-89C>T		upstream_gene	N/A	NP_877423.1	P33991
	MCM4	NM_005914.4		c.-205C>T		upstream_gene	N/A	NP_005905.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM4	ENST00000262105.6	TSL:1	c.-205C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000262105.2	P33991
	MCM4	ENST00000262105.6	TSL:1	c.-205C>T		5_prime_UTR	Exon 1 of 16	ENSP00000262105.2	P33991
	MCM4	ENST00000649838.1		c.-89C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000497648.1	A0A3B3IT92

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152180 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00434

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00322 AC: 1187 AN: 368678 Hom.: 7 Cov.: 5 AF XY: 0.00297 AC XY: 573 AN XY: 192792

African (AFR) AF: 0.000924 AC: 7 AN: 7578

American (AMR) AF: 0.000700 AC: 5 AN: 7140

Ashkenazi Jewish (ASJ) AF: 0.0000930 AC: 1 AN: 10754

East Asian (EAS) AF: 0.00 AC: 0 AN: 22036

South Asian (SAS) AF: 0.00 AC: 0 AN: 31338

European-Finnish (FIN) AF: 0.00106 AC: 29 AN: 27260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1668

European-Non Finnish (NFE) AF: 0.00458 AC: 1097 AN: 239630

Other (OTH) AF: 0.00226 AC: 48 AN: 21274

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152298 Hom.: 3 Cov.: 33 AF XY: 0.00217 AC XY: 162 AN XY: 74494

African (AFR) AF: 0.000842 AC: 35 AN: 41578

American (AMR) AF: 0.000523 AC: 8 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00434 AC: 295 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.00220

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	-0.72
CADD	Benign	0.14
DANN	Benign	0.67
PhyloP100		-3.2
PromoterAI		0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	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: rs17287526; hg19: chr8-48873500;