4-104491413-A-C

Variant names:

• chr4-104491413-A-C
• rs896194417
• NM_025212.4:c.390T>G
• CXXC4 p.Gly130Gly

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.390T>G​(p.Gly130Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000078 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000031 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CXXC4 NM_025212.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 4-104491413-A-C is Benign according to our data. Variant chr4-104491413-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2654991.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.249 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 26 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.390T>G	p.Gly130Gly	synonymous	Exon 2 of 3	NP_079488.2	J9JIF5
	CXXC4	NM_001440652.1		c.390T>G	p.Gly130Gly	synonymous	Exon 3 of 4	NP_001427581.1
	CXXC4-AS1	NR_125926.1		n.96+353A>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.390T>G	p.Gly130Gly	synonymous	Exon 2 of 3	ENSP00000378248.2	J9JIF5
	CXXC4	ENST00000466963.1	TSL:1	n.277+3093T>G		intron	N/A
	CXXC4	ENST00000698535.1		c.390T>G	p.Gly130Gly	synonymous	Exon 2 of 2	ENSP00000513781.1	A0A8V8TLX0

Frequencies

GnomAD3 genomes AF: 0.0000782 AC: 8 AN: 102338 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000369

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000181

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000313 AC: 26 AN: 829576 Hom.: 0 Cov.: 14 AF XY: 0.0000303 AC XY: 12 AN XY: 395696

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: 0.000484 AC: 7 AN: 14454

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: 0.0000272 AC: 19 AN: 697990

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

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000781 AC: 8 AN: 102384 Hom.: 0 Cov.: 24 AF XY: 0.0000405 AC XY: 2 AN XY: 49362

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

African (AFR) AF: 0.0000369 AC: 1 AN: 27122

American (AMR) AF: 0.000181 AC: 2 AN: 11074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2598

East Asian (EAS) AF: 0.00 AC: 0 AN: 3360

South Asian (SAS) AF: 0.00 AC: 0 AN: 2888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.000103 AC: 5 AN: 48366

Other (OTH) AF: 0.00 AC: 0 AN: 1362

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00295270), which strongly suggests a high chance of mosaicism in these individuals.

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	-0.61
CADD	Benign	8.2
DANN	Benign	0.44
PhyloP100		0.25
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs896194417; hg19: chr4-105412570; COSMIC: COSV67296270;