rs148337159

chr16-88805795-G-Achr16-88805795-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_030928.4(CDT1):c.758G>A(p.Arg253His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,613,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R253C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CDT1 NM_030928.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.74

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013385385).
• BP6: Variant 16-88805795-G-A is Benign according to our data. Variant chr16-88805795-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434675.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000768 (117/152326) while in subpopulation AFR AF= 0.00224 (93/41566). AF 95% confidence interval is 0.00187. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDT1	NM_030928.4	c.758G>A	p.Arg253His	missense_variant	5/10	ENST00000301019.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDT1	ENST00000301019.9	c.758G>A	p.Arg253His	missense_variant	5/10	1	NM_030928.4	P1
CDT1	ENST00000569140.1	c.29G>A	p.Arg10His	missense_variant	1/5	3
CDT1	ENST00000562747.1	n.464G>A		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152208 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000372 AC: 93 AN: 249804 Hom.: 0 AF XY: 0.000317 AC XY: 43 AN XY: 135546

Gnomad AFR exome AF: 0.00261

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000136 AC: 199 AN: 1460820 Hom.: 0 Cov.: 69 AF XY: 0.000139 AC XY: 101 AN XY: 726692

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152326 Hom.: 0 Cov.: 35 AF XY: 0.000738 AC XY: 55 AN XY: 74490

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000207 Hom.: 0

Bravo AF: 0.000839

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000297 AC: 36

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 24, 2017

- -

CDT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.71	N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.15
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.17
MVP		0.66
MPC		0.016
ClinPred		0.062	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.41

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: rs148337159; hg19: chr16-88872203;