16-88808268-A-T

Variant names:

• chr16-88808268-A-T
• rs144843732
• NM_030928.4:c.1631A>T

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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
• Publications: 3 publications found

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]

CDT1 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 4

  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: Benign. The variant received -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 VariationId is 128662.
• 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 the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030928.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDT1	NM_030928.4	MANE Select	c.1631A>T	p.Glu544Val	missense	Exon 10 of 10	NP_112190.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDT1	ENST00000301019.9	TSL:1 MANE Select	c.1631A>T	p.Glu544Val	missense	Exon 10 of 10	ENSP00000301019.4

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

GnomAD2 exomes AF: 0.00145 AC: 296 AN: 204448 AF XY: 0.00139

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 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

African (AFR) AF: 0.000242 AC: 8 AN: 33064

American (AMR) AF: 0.000637 AC: 26 AN: 40786

Ashkenazi Jewish (ASJ) AF: 0.000156 AC: 4 AN: 25568

East Asian (EAS) AF: 0.00 AC: 0 AN: 38628

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83288

European-Finnish (FIN) AF: 0.000658 AC: 33 AN: 50118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00370 AC: 4067 AN: 1100212

Other (OTH) AF: 0.00222 AC: 132 AN: 59440

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

African (AFR) AF: 0.000361 AC: 15 AN: 41570

American (AMR) AF: 0.000980 AC: 15 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00366 AC: 249 AN: 68006

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 17, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 17, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDT1: BP4

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.2
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
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs144843732; hg19: chr16-88874676; COSMIC: COSV99039908; COSMIC: COSV99039908;