Genetic Variant NM_025212.4:c.550T>C (chr4-104491253-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_025212.4(CXXC4):c.550T>C(p.Cys184Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CXXC4
NM_025212.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.12

Publications

0 publications found

Variant links:

Genes affected

CXXC4 (HGNC:24593): (CXXC finger protein 4) This gene encodes a CXXC-type zinc finger domain-containing protein that functions as an antagonist of the canonical wingless/integrated signaling pathway. The encoded protein negatively regulates wingless/integrated signaling through interaction with the post synaptic density protein/ Drosophila disc large tumor suppressor/ zonula occludens-1 protein domain of Dishevelled, a scaffolding protein required for the stabilization of the transcriptional co-activator beta-catenin. In addition, the CXXC domain of this protein has been shown to bind unmethylated CpG dinucleotides, localize to promoters and CpG islands, and interact with the catalytic domain of methylcytosine dioxygenase ten-eleven-translocation 2, an iron and alpha-ketoglutarate-dependent dioxygenase that modifies the methylation status of DNA. In humans, a mutation in this gene has been associated with development of malignant renal cell carcinoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

CXXC4 links:

CXXC4-AS1 (HGNC:41054): (CXXC4 antisense RNA 1)

CXXC4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.122691035).

BS2

High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025212.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CXXC4	NM_025212.4	MANE Select	c.550T>C	p.Cys184Arg	missense	Exon 2 of 3	NP_079488.2	J9JIF5
CXXC4	NM_001440652.1		c.550T>C	p.Cys184Arg	missense	Exon 3 of 4	NP_001427581.1
CXXC4-AS1	NR_125926.1		n.96+193A>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CXXC4	ENST00000394767.3	TSL:5 MANE Select	c.550T>C	p.Cys184Arg	missense	Exon 2 of 3	ENSP00000378248.2	J9JIF5
CXXC4	ENST00000466963.1	TSL:1	n.277+3253T>C		intron	N/A
CXXC4	ENST00000698535.1		c.550T>C	p.Cys184Arg	missense	Exon 2 of 2	ENSP00000513781.1	A0A8V8TLX0

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151472

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.00

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00000810

AC:

AN:

246826

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.0000642

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460992

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726768

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000396

AC:

AN:

151472

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73952

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41304

American (AMR)

AF:

0.000197

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5060

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67802

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000386

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.93

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.63

M_CAP

Benign

0.0041

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

PhyloP100

2.1

PrimateAI

Uncertain

0.73

REVEL

Benign

0.12

Sift4G

Benign

0.65

Vest4

0.29

MVP

0.14

ClinPred

0.16

GERP RS

2.4

gMVP

0.68

Mutation Taster

=80/20

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