Variant rs1057520299 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_018684.4(ZC4H2):c.53G>A(p.Arg18Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000893 in 111,923 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Consequence

ZC4H2
NM_018684.4 missense, splice_region

Scores

Splicing: ADA: 0.9925

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.23

Variant links:

Genes affected

ZC4H2 (HGNC:24931): (zinc finger C4H2-type containing) This gene encodes a member of the zinc finger domain-containing protein family. This family member has a C-terminal zinc finger domain that is characterized by four cysteine residues and two histidine residues, and it also includes a coiled-coil region. This protein has been detected as an autoantigen in hepatocellular carcinoma patients. This gene has been identified as a potential candidate for X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ZC4H2 links:

ZC4H2 (HGNC:):

ZC4H2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a chain Zinc finger C4H2 domain-containing protein (size 223) in uniprot entity ZC4H2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_018684.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

PP5

Variant X-64976325-C-T is Pathogenic according to our data. Variant chrX-64976325-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 378045.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC4H2	NM_018684.4 linkuse as main transcript	c.53G>A	p.Arg18Lys	missense_variant, splice_region_variant	1/5	ENST00000374839.8	NP_061154.1	Q9NQZ6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC4H2	ENST00000374839.8 linkuse as main transcript	c.53G>A	p.Arg18Lys	missense_variant, splice_region_variant	1/5	1	NM_018684.4	ENSP00000363972.3		Q9NQZ6-1

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111923

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34093

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000941

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111923

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34093

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000941

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Wieacker-Wolff syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;T

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.23

Sift

Benign

0.16

T;T

Sift4G

Uncertain

0.030

D;T

Polyphen

0.98

.;D

Vest4

0.76

MutPred

0.61

Gain of methylation at R18 (P = 0.0377);Gain of methylation at R18 (P = 0.0377);

MVP

0.62

MPC

1.6

ClinPred

0.97

GERP RS

4.7

Varity_R

0.68

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.88

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over