Variant 14-105011333-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017955.4(CDCA4):c.597G>T(p.Met199Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000861 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

CDCA4
NM_017955.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.54

Variant links:

Genes affected

CDCA4 (HGNC:14625): (cell division cycle associated 4) This gene encodes a protein that belongs to the E2F family of transcription factors. This protein regulates E2F-dependent transcriptional activation and cell proliferation, mainly through the E2F/retinoblastoma protein pathway. It also functions in the regulation of JUN oncogene expression. This protein shows distinctive nuclear-mitotic apparatus distribution, it is involved in spindle organization from prometaphase, and may also play a role as a midzone factor involved in chromosome segregation or cytokinesis. Two alternatively spliced transcript variants encoding the same protein have been noted for this gene. Two pseudogenes have also been identified on chromosome 1. [provided by RefSeq, May 2014]

CDCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030472279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDCA4	NM_017955.4 linkuse as main transcript	c.597G>T	p.Met199Ile	missense_variant	2/2	ENST00000336219.4
CDCA4	NM_145701.4 linkuse as main transcript	c.597G>T	p.Met199Ile	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDCA4	ENST00000336219.4 linkuse as main transcript	c.597G>T	p.Met199Ile	missense_variant	2/2	1	NM_017955.4	P1
CDCA4	ENST00000392590.3 linkuse as main transcript	c.597G>T	p.Met199Ile	missense_variant	2/3	1		P1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251060

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.0000787

AC:

115

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000749

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000158

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000172

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The c.597G>T (p.M199I) alteration is located in exon 2 (coding exon 1) of the CDCA4 gene. This alteration results from a G to T substitution at nucleotide position 597, causing the methionine (M) at amino acid position 199 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.036

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.71

.;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;M

MutationTaster

Benign

0.88

D;D

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.10

Sift

Benign

0.055

T;T

Sift4G

Benign

0.62

T;T

Polyphen

0.0020

B;B

Vest4

0.17

MutPred

0.32

Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);

MVP

0.27

MPC

0.20

ClinPred

0.049

GERP RS

3.8

Varity_R

0.23

gMVP

0.052

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over