NM_003504.5:c.112-7_112-4delTCTC

Variant names:

• chr22-19480940-ACTCT-A
• rs752245038
• NM_003504.5:c.112-7_112-4delTCTC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003504.5(CDC45):​c.112-7_112-4delTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,417,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDC45 NM_003504.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 0 publications found

Genes affected

CDC45 (HGNC:1739): (cell division cycle 45) The protein encoded by this gene was identified by its strong similarity with Saccharomyces cerevisiae Cdc45, an essential protein required to the initiation of DNA replication. Cdc45 is a member of the highly conserved multiprotein complex including Cdc6/Cdc18, the minichromosome maintenance proteins (MCMs) and DNA polymerase, which is important for early steps of DNA replication in eukaryotes. This protein has been shown to interact with MCM7 and DNA polymerase alpha. Studies of the similar gene in Xenopus suggested that this protein play a pivotal role in the loading of DNA polymerase alpha onto chromatin. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

CDC45 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003504.5. 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
	CDC45	NM_003504.5	MANE Select	c.112-7_112-4delTCTC		splice_region intron	N/A	NP_003495.1	O75419-1
	CDC45	NM_001178010.2		c.112-7_112-4delTCTC		splice_region intron	N/A	NP_001171481.1	O75419-3
	CDC45	NM_001369291.1		c.76-7_76-4delTCTC		splice_region intron	N/A	NP_001356220.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC45	ENST00000263201.7	TSL:1 MANE Select	c.112-12_112-9delCTCT		intron	N/A	ENSP00000263201.2	O75419-1
	CDC45	ENST00000437685.6	TSL:2	c.112-12_112-9delCTCT		intron	N/A	ENSP00000405726.2	O75419-3
	CDC45	ENST00000932444.1		c.112-12_112-9delCTCT		intron	N/A	ENSP00000602503.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1417022 Hom.: 0 AF XY: 0.00000142 AC XY: 1 AN XY: 706382

African (AFR) AF: 0.00 AC: 0 AN: 32284

American (AMR) AF: 0.00 AC: 0 AN: 42412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25396

East Asian (EAS) AF: 0.00 AC: 0 AN: 39092

South Asian (SAS) AF: 0.00 AC: 0 AN: 82656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077474

Other (OTH) AF: 0.00 AC: 0 AN: 58756

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.53		Position offset: -40
DS_AL_spliceai		0.69		Position offset: 13

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

Other links and lift over

dbSNP: rs752245038; hg19: chr22-19468463;