4-104472204-A-G

Variant names:

• chr4-104472204-A-G
• rs4413407
• ENST00000466963.1:n.440T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000466963.1(CXXC4):​n.440T>C variant causes a non coding transcript exon 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 ENST00000466963.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000466963.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXXC4	NM_025212.4	MANE Select	c.*118T>C		3_prime_UTR	Exon 3 of 3	NP_079488.2
	CXXC4	NR_132741.2		n.433T>C		non_coding_transcript_exon	Exon 3 of 3
	CXXC4	NM_001440652.1		c.*118T>C		3_prime_UTR	Exon 4 of 4	NP_001427581.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXXC4	ENST00000466963.1	TSL:1	n.440T>C		non_coding_transcript_exon	Exon 3 of 3
	CXXC4	ENST00000394767.3	TSL:5 MANE Select	c.*118T>C		3_prime_UTR	Exon 3 of 3	ENSP00000378248.2
	CXXC4	ENST00000515509.1	TSL:2	n.334T>C		non_coding_transcript_exon	Exon 2 of 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

African (AFR) AF: 0.922 AC: 8468 AN: 9186

American (AMR) AF: 0.560 AC: 9137 AN: 16330

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 7465 AN: 10422

East Asian (EAS) AF: 0.294 AC: 7903 AN: 26912

South Asian (SAS) AF: 0.667 AC: 9493 AN: 14240

European-Finnish (FIN) AF: 0.619 AC: 25020 AN: 40400

Middle Eastern (MID) AF: 0.706 AC: 1169 AN: 1656

European-Non Finnish (NFE) AF: 0.654 AC: 145652 AN: 222620

Other (OTH) AF: 0.664 AC: 13070 AN: 19698

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

African (AFR) AF: 0.920 AC: 36537 AN: 39728

American (AMR) AF: 0.604 AC: 8915 AN: 14756

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2554 AN: 3428

East Asian (EAS) AF: 0.331 AC: 1677 AN: 5066

South Asian (SAS) AF: 0.670 AC: 3124 AN: 4660

European-Finnish (FIN) AF: 0.607 AC: 5343 AN: 8800

Middle Eastern (MID) AF: 0.711 AC: 202 AN: 284

European-Non Finnish (NFE) AF: 0.664 AC: 44315 AN: 66786

Other (OTH) AF: 0.714 AC: 1453 AN: 2036

Alfa AF: 0.667 Hom.: 60736

Bravo AF: 0.725

Asia WGS AF: 0.519 AC: 1782 AN: 3434

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.9
DANN	Benign	0.69
PhyloP100		3.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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