Genetic Variant CDX4:p.Pro105Thr (chrX-73447566-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005193.2(CDX4):c.313C>A(p.Pro105Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000636 in 1,209,776 control chromosomes in the GnomAD database, including 1 homozygotes. There are 28 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.000044 ( 1 hom. 19 hem. )

Consequence

CDX4
NM_005193.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.47

Variant links:

Genes affected

CDX4 (HGNC:1808): (caudal type homeobox 4) This gene encodes a member of a small subfamily of homeobox containing transcription factors. The encoded protein may regulate homeobox gene expression during anteroposterior patterning and hematopoiesis. [provided by RefSeq, Aug 2012]

CDX4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03720796).

BS2

High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDX4	NM_005193.2 link	c.313C>A	p.Pro105Thr	missense_variant	Exon 1 of 3	ENST00000373514.3	NP_005184.1	O14627

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDX4	ENST00000373514.3 link	c.313C>A	p.Pro105Thr	missense_variant	Exon 1 of 3	1	NM_005193.2	ENSP00000362613.1		O14627

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

111830

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

AN XY:

34030

show subpopulations

Gnomad AFR

AF:

0.000812

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00134

GnomAD3 exomes

AF:

0.0000715

AC:

AN:

181764

Hom.:

AF XY:

0.0000450

AC XY:

AN XY:

66632

show subpopulations

Gnomad AFR exome

AF:

0.000928

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000437

AC:

AN:

1097892

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

363266

show subpopulations

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.000259

AC:

AN:

111884

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

AN XY:

34094

show subpopulations

Gnomad4 AFR

AF:

0.000843

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00132

Alfa

AF:

0.0000167

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313C>A (p.P105T) alteration is located in exon 1 (coding exon 1) of the CDX4 gene. This alteration results from a C to A substitution at nucleotide position 313, causing the proline (P) at amino acid position 105 to be replaced by a threonine (T). 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

Benign

0.068

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.17

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.56

M_CAP

Benign

0.0076

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.2

REVEL

Benign

0.094

Sift

Uncertain

0.021

Sift4G

Uncertain

0.022

Polyphen

0.19

Vest4

0.14

MVP

0.79

MPC

0.30

ClinPred

0.078

GERP RS

1.7

Varity_R

0.15

gMVP

0.56

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