X-64919176-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_018684.4(ZC4H2):c.427C>A(p.Gln143Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,791 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Consequence

ZC4H2
NM_018684.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.66

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Wieacker-Wolff syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Wieacker-Wolff syndrome, female-restricted
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ZC4H2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a chain Zinc finger C4H2 domain-containing protein (size 223) in uniprot entity ZC4H2_HUMAN there are 21 pathogenic changes around while only 7 benign (75%) in NM_018684.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3185876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC4H2	NM_018684.4 link	c.427C>A	p.Gln143Lys	missense_variant	Exon 4 of 5	ENST00000374839.8	NP_061154.1	Q9NQZ6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC4H2	ENST00000374839.8 link	c.427C>A	p.Gln143Lys	missense_variant	Exon 4 of 5	1	NM_018684.4	ENSP00000363972.3		Q9NQZ6-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111791

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000949

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111791

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33981

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30715

American (AMR)

AF:

0.0000949

AC:

AN:

10541

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.00

AC:

AN:

2654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6051

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53203

Other (OTH)

AF:

0.00

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.427C>A (p.Q143K) alteration is located in exon 4 (coding exon 4) of the ZC4H2 gene. This alteration results from a C to A substitution at nucleotide position 427, causing the glutamine (Q) at amino acid position 143 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.056

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.35

N;.

PhyloP100

9.7

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.56

N;N

REVEL

Benign

0.21

Sift

Benign

0.30

T;T

Sift4G

Benign

0.96

T;T

Polyphen

0.88

P;.

Vest4

0.58

MutPred

0.48

Gain of methylation at Q143 (P = 0.0033);.;

MVP

0.54

MPC

0.0020

ClinPred

0.53

GERP RS

5.4

Varity_R

0.60

gMVP

0.68

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over