4-104491428-T-G

Variant names:

• chr4-104491428-T-G
• rs1303327222
• NM_025212.4:c.375A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_025212.4(CXXC4):​c.375A>C​(p.Gly125Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 823,242 control chromosomes in the GnomAD database, including 4 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. Synonymous variant affecting the same amino acid position (i.e. G125G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (1 hom., cov: 26)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: CXXC4 NM_025212.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BS2: High AC in GnomAd4 at 553 AD gene.

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.375A>C	p.Gly125Gly	synonymous	Exon 2 of 3	NP_079488.2	J9JIF5
	CXXC4	NM_001440652.1		c.375A>C	p.Gly125Gly	synonymous	Exon 3 of 4	NP_001427581.1
	CXXC4-AS1	NR_125926.1		n.96+368T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXXC4	ENST00000394767.3	TSL:5 MANE Select	c.375A>C	p.Gly125Gly	synonymous	Exon 2 of 3	ENSP00000378248.2	J9JIF5
	CXXC4	ENST00000466963.1	TSL:1	n.277+3078A>C		intron	N/A
	CXXC4	ENST00000698535.1		c.375A>C	p.Gly125Gly	synonymous	Exon 2 of 2	ENSP00000513781.1	A0A8V8TLX0

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 552 AN: 118164 Hom.: 1 Cov.: 26

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.000337

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000894

Gnomad FIN AF: 0.000496

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000585

Gnomad OTH AF: 0.00301

GnomAD2 exomes AF: 0.00 AC: 0 AN: 144 AF XY: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

GnomAD4 exome AF: 0.00125 AC: 879 AN: 705044 Hom.: 3 Cov.: 12 AF XY: 0.00120 AC XY: 405 AN XY: 336520

African (AFR) AF: 0.0138 AC: 203 AN: 14696

American (AMR) AF: 0.00341 AC: 19 AN: 5576

Ashkenazi Jewish (ASJ) AF: 0.000107 AC: 1 AN: 9378

East Asian (EAS) AF: 0.000260 AC: 5 AN: 19250

South Asian (SAS) AF: 0.000629 AC: 8 AN: 12712

European-Finnish (FIN) AF: 0.000317 AC: 5 AN: 15794

Middle Eastern (MID) AF: 0.00207 AC: 4 AN: 1928

European-Non Finnish (NFE) AF: 0.000974 AC: 582 AN: 597368

Other (OTH) AF: 0.00183 AC: 52 AN: 28342

GnomAD4 genome AF: 0.00468 AC: 553 AN: 118198 Hom.: 1 Cov.: 26 AF XY: 0.00467 AC XY: 269 AN XY: 57548

African (AFR) AF: 0.0149 AC: 480 AN: 32284

American (AMR) AF: 0.00229 AC: 29 AN: 12644

Ashkenazi Jewish (ASJ) AF: 0.000337 AC: 1 AN: 2970

East Asian (EAS) AF: 0.00 AC: 0 AN: 3666

South Asian (SAS) AF: 0.000897 AC: 3 AN: 3344

European-Finnish (FIN) AF: 0.000496 AC: 3 AN: 6048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 204

European-Non Finnish (NFE) AF: 0.000585 AC: 32 AN: 54700

Other (OTH) AF: 0.00299 AC: 5 AN: 1674

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.3
DANN	Benign	0.55
PhyloP100		-1.2

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: rs1303327222; hg19: chr4-105412585;