Genetic Variant NM_025212.4:c.375A>G (chr4-104491428-T-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

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

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.24

Publications

0 publications found

Variant links:

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 links:

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

CXXC4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

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

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:

AN:

118172

Hom.:

Cov.:

show subpopulations

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:

AN:

705170

Hom.:

Cov.:

AF XY:

0.0000891

AC XY:

AN XY:

336574

show subpopulations

African (AFR)

AF:

0.000136

AC:

AN:

14700

American (AMR)

AF:

0.000179

AC:

AN:

5576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9378

East Asian (EAS)

AF:

0.000104

AC:

AN:

19250

South Asian (SAS)

AF:

0.0000787

AC:

AN:

12704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1930

European-Non Finnish (NFE)

AF:

0.0000921

AC:

AN:

597488

Other (OTH)

AF:

0.0000706

AC:

AN:

28348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000178

AC:

AN:

118172

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

57508

show subpopulations

African (AFR)

AF:

0.000372

AC:

AN:

32244

American (AMR)

AF:

0.00

AC:

AN:

12628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2970

East Asian (EAS)

AF:

0.00

AC:

AN:

3684

South Asian (SAS)

AF:

0.00

AC:

AN:

3358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.000165

AC:

AN:

54706

Other (OTH)

AF:

0.00

AC:

AN:

1660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.8

(source)

DANN

Benign

0.39

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over