rs144843732

Positions:

• chr16-88808268-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_030928.4(CDT1):​c.1631A>T​(p.Glu544Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,589,160 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. E544D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 35)
  • Exomes 𝑓: 0.0030 (14 hom.)
• Consequence: CDT1 NM_030928.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.15

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067598224).
• BP6: Variant 16-88808268-A-T is Benign according to our data. Variant chr16-88808268-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128662.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}. Variant chr16-88808268-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00186 (284/152306) while in subpopulation NFE AF= 0.00366 (249/68006). AF 95% confidence interval is 0.00329. There are 1 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDT1	NM_030928.4	c.1631A>T	p.Glu544Val	missense_variant	10/10	ENST00000301019.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDT1	ENST00000301019.9	c.1631A>T	p.Glu544Val	missense_variant	10/10	1	NM_030928.4	P1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152188 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00145 AC: 296 AN: 204448 Hom.: 0 AF XY: 0.00139 AC XY: 154 AN XY: 110658

Gnomad AFR exome AF: 0.000415

Gnomad AMR exome AF: 0.000645

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000284

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00210

GnomAD4 exome AF: 0.00297 AC: 4271 AN: 1436854 Hom.: 14 Cov.: 34 AF XY: 0.00285 AC XY: 2034 AN XY: 712668

Gnomad4 AFR exome AF: 0.000242

Gnomad4 AMR exome AF: 0.000637

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.000658

Gnomad4 NFE exome AF: 0.00370

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00186 AC: 284 AN: 152306 Hom.: 1 Cov.: 35 AF XY: 0.00148 AC XY: 110 AN XY: 74486

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00366

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00264 Hom.: 1

Bravo AF: 0.00184

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000458 AC: 2

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00128 AC: 154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	The E544V variant in the CDT1 gene has been published previously in a single individual with abnormality of growth (Retterer et al., 2016). The E544V variant is observed in 290/102030 (0.28%) alleles from individuals of non-Finnish European background in large population cohorts, and one individual is reported to be homozygous (Lek et al., 2016). The E544V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret E544V as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CDT1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 17, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.15
MVP		0.79
MPC		0.013
ClinPred		0.054	T
GERP RS		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144843732; hg19: chr16-88874676; COSMIC: COSV99039908; COSMIC: COSV99039908;