Variant 4-104491428-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_025212.4(CXXC4):c.375A>G(p.Gly125Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 823,342 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

CXXC4
NM_025212.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.24

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 (HGNC:):

CXXC4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 4-104491428-T-C is Benign according to our data. Variant chr4-104491428-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3388909.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.24 with no splicing effect.

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXXC4	NM_025212.4 linkuse as main transcript	c.375A>G	p.Gly125Gly	synonymous_variant	2/3	ENST00000394767.3	NP_079488.2	J9JIF5
CXXC4	XM_011532284.3 linkuse as main transcript	c.375A>G	p.Gly125Gly	synonymous_variant	3/4		XP_011530586.1	J9JIF5
CXXC4-AS1	NR_125926.1 linkuse as main transcript	n.96+368T>C		intron_variant
CXXC4	NR_132741.2 linkuse as main transcript	n.270+3078A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXXC4	ENST00000394767.3 linkuse as main transcript	c.375A>G	p.Gly125Gly	synonymous_variant	2/3	5	NM_025212.4	ENSP00000378248.2		J9JIF5

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

118172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000372

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:

0.000165

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000893

AC:

AN:

705170

Hom.:

Cov.:

AF XY:

0.0000891

AC XY:

AN XY:

336574

show subpopulations

Gnomad4 AFR exome

AF:

0.000136

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000104

Gnomad4 SAS exome

AF:

0.0000787

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000921

Gnomad4 OTH exome

AF:

0.0000706

GnomAD4 genome

AF:

0.000178

AC:

AN:

118172

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

57508

show subpopulations

Gnomad4 AFR

AF:

0.000372

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:

0.000165

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

CXXC4: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.8

DANN

Benign

0.39

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