rs480727

Variant names:

• chr16-88805821-A-G
• rs480727
• NM_030928.4:c.784A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030928.4(CDT1):​c.784A>G​(p.Thr262Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 1,612,382 control chromosomes in the GnomAD database, including 139,935 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.50 (20328 hom., cov: 34)
  • Exomes 𝑓: 0.39 (119607 hom.)
• Consequence: CDT1 NM_030928.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.464
• Publications: 45 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8148388E-6).
• BP6: Variant 16-88805821-A-G is Benign according to our data. Variant chr16-88805821-A-G is described in ClinVar as Benign. ClinVar VariationId is 128682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDT1	NM_030928.4	c.784A>G	p.Thr262Ala	missense_variant	Exon 5 of 10	ENST00000301019.9	NP_112190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDT1	ENST00000301019.9	c.784A>G	p.Thr262Ala	missense_variant	Exon 5 of 10	1	NM_030928.4	ENSP00000301019.4
CDT1	ENST00000569140.1	c.52A>G	p.Thr18Ala	missense_variant	Exon 1 of 5	3		ENSP00000456926.1
CDT1	ENST00000562747.1	n.490A>G		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75285 AN: 151988 Hom.: 20293 Cov.: 34

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.525

GnomAD2 exomes AF: 0.442 AC: 109875 AN: 248612 AF XY: 0.435

Gnomad AFR exome AF: 0.710

Gnomad AMR exome AF: 0.433

Gnomad ASJ exome AF: 0.524

Gnomad EAS exome AF: 0.721

Gnomad FIN exome AF: 0.343

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.444

GnomAD4 exome AF: 0.395 AC: 576183 AN: 1460278 Hom.: 119607 Cov.: 65 AF XY: 0.395 AC XY: 287245 AN XY: 726404

African (AFR) AF: 0.725 AC: 24257 AN: 33472

American (AMR) AF: 0.445 AC: 19835 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 13677 AN: 26132

East Asian (EAS) AF: 0.735 AC: 29161 AN: 39680

South Asian (SAS) AF: 0.417 AC: 35967 AN: 86218

European-Finnish (FIN) AF: 0.342 AC: 17931 AN: 52430

Middle Eastern (MID) AF: 0.552 AC: 3143 AN: 5692

European-Non Finnish (NFE) AF: 0.365 AC: 405774 AN: 1111698

Other (OTH) AF: 0.438 AC: 26438 AN: 60354

GnomAD4 genome AF: 0.495 AC: 75367 AN: 152104 Hom.: 20328 Cov.: 34 AF XY: 0.493 AC XY: 36673 AN XY: 74346

African (AFR) AF: 0.705 AC: 29257 AN: 41498

American (AMR) AF: 0.472 AC: 7208 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1830 AN: 3470

East Asian (EAS) AF: 0.719 AC: 3714 AN: 5166

South Asian (SAS) AF: 0.417 AC: 2011 AN: 4818

European-Finnish (FIN) AF: 0.344 AC: 3645 AN: 10584

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25965 AN: 67968

Other (OTH) AF: 0.520 AC: 1098 AN: 2110

Alfa AF: 0.426 Hom.: 63833

Bravo AF: 0.518

TwinsUK AF: 0.366 AC: 1356

ALSPAC AF: 0.355 AC: 1367

ESP6500AA AF: 0.713 AC: 3130

ESP6500EA AF: 0.384 AC: 3304

ExAC AF: 0.442 AC: 53552

Asia WGS AF: 0.574 AC: 1997 AN: 3478

EpiCase AF: 0.397

EpiControl AF: 0.407

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meier-Gorlin syndrome 4 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.69
DANN	Benign	0.43
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.029	T
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.080	N
PhyloP100		-0.46
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.0060
Sift	Benign	0.72	T
Sift4G	Benign	0.84	T
Polyphen		0.0030	B
Vest4		0.012
MPC		0.013
ClinPred		0.0017	T
GERP RS		-1.3
PromoterAI		0.060	Neutral
Varity_R		0.024
gMVP		0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs480727; hg19: chr16-88872229; COSMIC: COSV56349614; COSMIC: COSV56349614;