rs763750056

Variant names:

• chr4-104472348-C-A
• rs763750056
• NM_025212.4:c.1078G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-104472348-C-A
• chr4-104472348-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025212.4(CXXC4):​c.1078G>T​(p.Ala360Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A360T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CXXC4 NM_025212.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27736735).

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.1078G>T	p.Ala360Ser	missense	Exon 3 of 3	NP_079488.2	J9JIF5
	CXXC4	NM_001440652.1		c.1078G>T	p.Ala360Ser	missense	Exon 4 of 4	NP_001427581.1
	CXXC4	NR_132741.2		n.289G>T		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXXC4	ENST00000394767.3	TSL:5 MANE Select	c.1078G>T	p.Ala360Ser	missense	Exon 3 of 3	ENSP00000378248.2	J9JIF5
	CXXC4	ENST00000466963.1	TSL:1	n.296G>T		non_coding_transcript_exon	Exon 3 of 3
	CXXC4	ENST00000515509.1	TSL:2	n.190G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452648 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722518

⚠️ 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: 32962

American (AMR) AF: 0.00 AC: 0 AN: 43936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.00 AC: 0 AN: 84532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106850

Other (OTH) AF: 0.0000167 AC: 1 AN: 59984

⚠️ 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.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.97
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.50	T
PhyloP100		2.9
PrimateAI	Uncertain	0.72	T
REVEL	Benign	0.16
Sift4G	Uncertain	0.021	D
Vest4		0.52
MVP		0.030
ClinPred		0.87	D
GERP RS		4.5
gMVP		0.60
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs763750056; hg19: chr4-105393505;