rs3218729

Positions:

• chr16-88807372-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030928.4(CDT1):​c.1367A>C​(p.Glu456Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00173 in 1,612,664 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0061 (10 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (21 hom.)
• Consequence: CDT1 NM_030928.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.55

Genes affected

CDT1 (HGNC:24576): (chromatin licensing and DNA replication factor 1) The protein encoded by this gene is involved in the formation of the pre-replication complex that is necessary for DNA replication. The encoded protein can bind geminin, which prevents replication and may function to prevent this protein from initiating replication at inappropriate origins. Phosphorylation of this protein by cyclin A-dependent kinases results in degradation of the protein. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009843707).
• BP6: Variant 16-88807372-A-C is Benign according to our data. Variant chr16-88807372-A-C is described in ClinVar as [Benign]. Clinvar id is 128668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00606 (924/152364) while in subpopulation AFR AF= 0.0195 (809/41588). AF 95% confidence interval is 0.0183. There are 10 homozygotes in gnomad4. There are 451 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDT1	NM_030928.4	c.1367A>C	p.Glu456Ala	missense_variant	9/10	ENST00000301019.9	NP_112190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDT1	ENST00000301019.9	c.1367A>C	p.Glu456Ala	missense_variant	9/10	1	NM_030928.4	ENSP00000301019.4
CDT1	ENST00000569140.1	c.*30A>C		downstream_gene_variant		3		ENSP00000456926.1

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 906 AN: 152246 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00285 AC: 706 AN: 247288 Hom.: 9 AF XY: 0.00303 AC XY: 408 AN XY: 134774

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000630

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00128 AC: 1871 AN: 1460300 Hom.: 21 Cov.: 33 AF XY: 0.00150 AC XY: 1087 AN XY: 726474

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00606 AC: 924 AN: 152364 Hom.: 10 Cov.: 34 AF XY: 0.00605 AC XY: 451 AN XY: 74510

Gnomad4 AFR AF: 0.0195

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00137 Hom.: 1

Bravo AF: 0.00665

ESP6500AA AF: 0.0198 AC: 87

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00352 AC: 426

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.37
Sift	Benign	0.097	T
Sift4G	Benign	0.14	T
Polyphen		0.72	P
Vest4		0.55
MVP		0.91
MPC		0.057
ClinPred		0.049	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs3218729; hg19: chr16-88873780;