chr4-104491467-G-C

Position:

• chr4-104491467-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_025212.4(CXXC4):​c.336C>G​(p.Gly112=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CXXC4 NM_025212.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.341

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)

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 4-104491467-G-C is Benign according to our data. Variant chr4-104491467-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2654996.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.341 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CXXC4	NM_025212.4	c.336C>G	p.Gly112=	synonymous_variant	2/3	ENST00000394767.3
CXXC4-AS1	NR_125926.1	n.96+407G>C		intron_variant, non_coding_transcript_variant
CXXC4	XM_011532284.3	c.336C>G	p.Gly112=	synonymous_variant	3/4
CXXC4	NR_132741.2	n.270+3039C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CXXC4	ENST00000394767.3	c.336C>G	p.Gly112=	synonymous_variant	2/3	5	NM_025212.4	P2
CXXC4-AS1	ENST00000500179.1	n.96+407G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 23 AN: 134970 Hom.: 0 Cov.: 27 FAILED QC

Gnomad AFR AF: 0.000155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000539

Gnomad FIN AF: 0.000733

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000323

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00244 AC: 1062 AN: 435500 Hom.: 0 Cov.: 9 AF XY: 0.00248 AC XY: 518 AN XY: 208574

Gnomad4 AFR exome AF: 0.00139

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000867

Gnomad4 EAS exome AF: 0.000238

Gnomad4 SAS exome AF: 0.00340

Gnomad4 FIN exome AF: 0.000127

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000170 AC: 23 AN: 135064 Hom.: 0 Cov.: 27 AF XY: 0.000215 AC XY: 14 AN XY: 65254

Gnomad4 AFR AF: 0.000155

Gnomad4 AMR AF: 0.000215

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000537

Gnomad4 FIN AF: 0.000733

Gnomad4 NFE AF: 0.0000323

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

CXXC4: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.7
DANN	Benign	0.62

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

Other links and lift over

dbSNP: rs1032157514; hg19: chr4-105412624;