GeneBe

4-104472204-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000466963.1(CXXC4):​n.440T>A variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.00000393 in 509,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 24)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CXXC4
ENST00000466963.1 non_coding_transcript_exon

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.76

Publications

5 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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.55).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CXXC4NM_025212.4 linkc.*118T>A 3_prime_UTR_variant Exon 3 of 3 ENST00000394767.3 NP_079488.2 J9JIF5
CXXC4NR_132741.2 linkn.433T>A non_coding_transcript_exon_variant Exon 3 of 3
CXXC4NM_001440652.1 linkc.*118T>A 3_prime_UTR_variant Exon 4 of 4 NP_001427581.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CXXC4ENST00000466963.1 linkn.440T>A non_coding_transcript_exon_variant Exon 3 of 3 1
CXXC4ENST00000394767.3 linkc.*118T>A 3_prime_UTR_variant Exon 3 of 3 5 NM_025212.4 ENSP00000378248.2 J9JIF5
CXXC4ENST00000515509.1 linkn.334T>A non_coding_transcript_exon_variant Exon 2 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.00000682
AC:
1
AN:
146546
Hom.:
0
Cov.:
24
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000113
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000276
AC:
1
AN:
362506
Hom.:
0
Cov.:
6
AF XY:
0.00
AC XY:
0
AN XY:
191346
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
9194
American (AMR)
AF:
0.00
AC:
0
AN:
16368
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
10448
East Asian (EAS)
AF:
0.00
AC:
0
AN:
26974
South Asian (SAS)
AF:
0.0000700
AC:
1
AN:
14280
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40506
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1656
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
223304
Other (OTH)
AF:
0.00
AC:
0
AN:
19776
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000682
AC:
1
AN:
146546
Hom.:
0
Cov.:
24
AF XY:
0.0000141
AC XY:
1
AN XY:
71172
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
39672
American (AMR)
AF:
0.00
AC:
0
AN:
14762
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3434
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5084
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4692
European-Finnish (FIN)
AF:
0.000113
AC:
1
AN:
8826
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
310
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
66842
Other (OTH)
AF:
0.00
AC:
0
AN:
2020
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
60736

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.55
CADD
Benign
7.5
DANN
Benign
0.65
PhyloP100
3.8
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs4413407; hg19: chr4-105393361; API