rs4413407

Positions:

• chr4-104472204-A-G
• chr4-104472204-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025212.4(CXXC4):​c.*118T>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.654 in 507,912 control chromosomes in the GnomAD database, including 114,112 homozygotes. 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 0.72 (39104 hom., cov: 24)
  • Exomes 𝑓: 0.63 (75008 hom.)
• Consequence: CXXC4 NM_025212.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXXC4	NM_025212.4	c.*118T>C		3_prime_UTR_variant	3/3	ENST00000394767.3	NP_079488.2
CXXC4	XM_011532284.3	c.*118T>C		3_prime_UTR_variant	4/4		XP_011530586.1
CXXC4	NR_132741.2	n.433T>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXXC4	ENST00000394767	c.*118T>C		3_prime_UTR_variant	3/3	5	NM_025212.4	ENSP00000378248.2
CXXC4	ENST00000466963.1	n.440T>C		non_coding_transcript_exon_variant	3/3	1
CXXC4	ENST00000515509.1	n.334T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.715 AC: 104714 AN: 146408 Hom.: 39085 Cov.: 24

Gnomad AFR AF: 0.920

Gnomad AMI AF: 0.692

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.710

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.717

GnomAD4 exome AF: 0.629 AC: 227377 AN: 361464 Hom.: 75008 Cov.: 6 AF XY: 0.632 AC XY: 120673 AN XY: 190788

Gnomad4 AFR exome AF: 0.922

Gnomad4 AMR exome AF: 0.560

Gnomad4 ASJ exome AF: 0.716

Gnomad4 EAS exome AF: 0.294

Gnomad4 SAS exome AF: 0.667

Gnomad4 FIN exome AF: 0.619

Gnomad4 NFE exome AF: 0.654

Gnomad4 OTH exome AF: 0.664

GnomAD4 genome AF: 0.715 AC: 104746 AN: 146448 Hom.: 39104 Cov.: 24 AF XY: 0.708 AC XY: 50407 AN XY: 71162

Gnomad4 AFR AF: 0.920

Gnomad4 AMR AF: 0.604

Gnomad4 ASJ AF: 0.745

Gnomad4 EAS AF: 0.331

Gnomad4 SAS AF: 0.670

Gnomad4 FIN AF: 0.607

Gnomad4 NFE AF: 0.664

Gnomad4 OTH AF: 0.714

Alfa AF: 0.647 Hom.: 9974

Bravo AF: 0.725

Asia WGS AF: 0.519 AC: 1782 AN: 3434

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.9
DANN	Benign	0.69

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: rs4413407; hg19: chr4-105393361; COSMIC: COSV67296699;