4-104491428-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_025212.4(CXXC4):​c.375A>G​(p.Gly125Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 823,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: CXXC4 NM_025212.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 4-104491428-T-C is Benign according to our data. Variant chr4-104491428-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3388909.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BS2: High AC in GnomAd4 at 21 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>G	p.Gly125Gly	synonymous	Exon 2 of 3	NP_079488.2	J9JIF5
	CXXC4	NM_001440652.1		c.375A>G	p.Gly125Gly	synonymous	Exon 3 of 4	NP_001427581.1
	CXXC4-AS1	NR_125926.1		n.96+368T>C		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>G	p.Gly125Gly	synonymous	Exon 2 of 3	ENSP00000378248.2	J9JIF5
	CXXC4	ENST00000466963.1	TSL:1	n.277+3078A>G		intron	N/A
	CXXC4	ENST00000698535.1		c.375A>G	p.Gly125Gly	synonymous	Exon 2 of 2	ENSP00000513781.1	A0A8V8TLX0

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 21 AN: 118172 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000165

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000893 AC: 63 AN: 705170 Hom.: 0 Cov.: 12 AF XY: 0.0000891 AC XY: 30 AN XY: 336574

African (AFR) AF: 0.000136 AC: 2 AN: 14700

American (AMR) AF: 0.000179 AC: 1 AN: 5576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9378

East Asian (EAS) AF: 0.000104 AC: 2 AN: 19250

South Asian (SAS) AF: 0.0000787 AC: 1 AN: 12704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1930

European-Non Finnish (NFE) AF: 0.0000921 AC: 55 AN: 597488

Other (OTH) AF: 0.0000706 AC: 2 AN: 28348

GnomAD4 genome AF: 0.000178 AC: 21 AN: 118172 Hom.: 0 Cov.: 26 AF XY: 0.000122 AC XY: 7 AN XY: 57508

African (AFR) AF: 0.000372 AC: 12 AN: 32244

American (AMR) AF: 0.00 AC: 0 AN: 12628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2970

East Asian (EAS) AF: 0.00 AC: 0 AN: 3684

South Asian (SAS) AF: 0.00 AC: 0 AN: 3358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.000165 AC: 9 AN: 54706

Other (OTH) AF: 0.00 AC: 0 AN: 1660

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.8
DANN	Benign	0.39
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

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;