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chr4-104491171-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_025212.4(CXXC4):ā€‹c.632G>Cā€‹(p.Gly211Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

CXXC4
NM_025212.4 missense

Scores

1
6
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.84
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-AS1 (HGNC:41054): (CXXC4 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3220496).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CXXC4NM_025212.4 linkuse as main transcriptc.632G>C p.Gly211Ala missense_variant 2/3 ENST00000394767.3
CXXC4-AS1NR_125926.1 linkuse as main transcriptn.96+111C>G intron_variant, non_coding_transcript_variant
CXXC4XM_011532284.3 linkuse as main transcriptc.632G>C p.Gly211Ala missense_variant 3/4
CXXC4NR_132741.2 linkuse as main transcriptn.270+3335G>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CXXC4ENST00000394767.3 linkuse as main transcriptc.632G>C p.Gly211Ala missense_variant 2/35 NM_025212.4 P2
CXXC4-AS1ENST00000500179.1 linkuse as main transcriptn.96+111C>G intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251226
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135852
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
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:
0.00000137
AC:
2
AN:
1461754
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727158
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

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 submitterclinical testingAmbry GeneticsMay 24, 2023The c.125G>C (p.G42A) alteration is located in exon 1 (coding exon 1) of the CXXC4 gene. This alteration results from a G to C substitution at nucleotide position 125, causing the glycine (G) at amino acid position 42 to be replaced by an alanine (A). 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
BayesDel_addAF
Uncertain
0.037
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
23
DANN
Uncertain
0.99
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.0081
T
MetaRNN
Benign
0.32
T
MetaSVM
Benign
-0.74
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.80
D
REVEL
Uncertain
0.30
Sift4G
Benign
0.19
T
Vest4
0.51
MVP
0.030
ClinPred
0.99
D
GERP RS
3.6
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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.

Other links and lift over

dbSNP: rs1560544374; hg19: chr4-105412328; API