4-104491413-A-T

Variant names:

• chr4-104491413-A-T
• rs896194417
• NM_025212.4:c.390T>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_025212.4(CXXC4):​c.390T>A​(p.Gly130Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000121 in 829,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G130G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: CXXC4 NM_025212.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.249
• Publications: 0 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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP7: Synonymous conserved (PhyloP=0.249 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025212.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXXC4	NM_025212.4	MANE Select	c.390T>A	p.Gly130Gly	synonymous	Exon 2 of 3	NP_079488.2	J9JIF5
	CXXC4	NM_001440652.1		c.390T>A	p.Gly130Gly	synonymous	Exon 3 of 4	NP_001427581.1
	CXXC4-AS1	NR_125926.1		n.96+353A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXXC4	ENST00000394767.3	TSL:5 MANE Select	c.390T>A	p.Gly130Gly	synonymous	Exon 2 of 3	ENSP00000378248.2	J9JIF5
	CXXC4	ENST00000466963.1	TSL:1	n.277+3093T>A		intron	N/A
	CXXC4	ENST00000698535.1		c.390T>A	p.Gly130Gly	synonymous	Exon 2 of 2	ENSP00000513781.1	A0A8V8TLX0

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000121 AC: 1 AN: 829588 Hom.: 0 Cov.: 14 AF XY: 0.00000253 AC XY: 1 AN XY: 395706

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17532

American (AMR) AF: 0.00 AC: 0 AN: 7328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11774

East Asian (EAS) AF: 0.00 AC: 0 AN: 23922

South Asian (SAS) AF: 0.00 AC: 0 AN: 14462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2362

European-Non Finnish (NFE) AF: 0.00000143 AC: 1 AN: 697994

Other (OTH) AF: 0.00 AC: 0 AN: 34262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.5
DANN	Benign	0.71
PhyloP100		0.25

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: rs896194417; hg19: chr4-105412570;