Genetic Variant CDX4:p.Pro40Thr (chrX-73447371-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_005193.2(CDX4):c.118C>A(p.Pro40Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000587 in 1,208,619 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000090 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000056 ( 0 hom. 27 hem. )

Consequence

CDX4
NM_005193.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.67

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant X-73447371-C-A is Benign according to our data. Variant chrX-73447371-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2464621.

BS2

High Hemizygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005193.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDX4	NM_005193.2	MANE Select	c.118C>A	p.Pro40Thr	missense	Exon 1 of 3	NP_005184.1	O14627

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDX4	ENST00000373514.3	TSL:1 MANE Select	c.118C>A	p.Pro40Thr	missense	Exon 1 of 3	ENSP00000362613.1	O14627
	CDX4	ENST00000911265.1		c.118C>A	p.Pro40Thr	missense	Exon 1 of 4	ENSP00000581324.1

Frequencies

GnomAD3 genomes

AF:

0.0000901

AC:

AN:

110939

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000660

AC:

AN:

181764

AF XY:

0.0000753

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000136

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000556

AC:

AN:

1097680

Hom.:

Cov.:

AF XY:

0.0000744

AC XY:

AN XY:

363074

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26394

American (AMR)

AF:

0.0000569

AC:

AN:

35177

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19371

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.00

AC:

AN:

54071

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40463

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000653

AC:

AN:

841806

Other (OTH)

AF:

0.0000651

AC:

AN:

46065

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000901

AC:

AN:

110939

Hom.:

Cov.:

AF XY:

0.0000904

AC XY:

AN XY:

33195

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30510

American (AMR)

AF:

0.000286

AC:

AN:

10506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2630

East Asian (EAS)

AF:

0.00

AC:

AN:

3482

South Asian (SAS)

AF:

0.00

AC:

AN:

2573

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

52868

Other (OTH)

AF:

0.00

AC:

AN:

1479

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.55

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.3

PhyloP100

2.7

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.31

Sift

Uncertain

0.010

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.35

MutPred

0.53

Gain of phosphorylation at P40 (P = 0.0333)

MVP

0.69

MPC

0.39

ClinPred

0.29

GERP RS

2.5

PromoterAI

0.012

Neutral

(source)

Varity_R

0.39

gMVP

0.55

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over