rs1131691616

Variant names:

• chrX-64921843-G-A
• rs1131691616
• NM_018684.4:c.199C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018684.4(ZC4H2):​c.199C>T​(p.Arg67*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZC4H2 NM_018684.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.87

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-64921843-G-A is Pathogenic according to our data. Variant chrX-64921843-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-64921843-G-A is described in Lovd as [Pathogenic]. Variant chrX-64921843-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC4H2	NM_018684.4	c.199C>T	p.Arg67*	stop_gained	Exon 2 of 5	ENST00000374839.8	NP_061154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC4H2	ENST00000374839.8	c.199C>T	p.Arg67*	stop_gained	Exon 2 of 5	1	NM_018684.4	ENSP00000363972.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wieacker-Wolff syndrome, female-restricted Pathogenic:2

-

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Heterozygous Nonsense variant c.199C>T in Exon 2 of the ZC4H2 gene that results in the amino acid substitution p.Arg67* was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/ Likely Pathogenic [Variation ID:429826]. The observed variant has been previously reported in patients affected with arthrogryposis multiplex congenita (Frints, Suzanna G M et al., 2019). For these reasons, this variant has been classified as Pathogenic. -

Jan 24, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Arg67Ter variant in ZC4H2 was identified by our study in one individual with female-restricted Wieacker-Wolff syndrome. Trio exome analysis showed this variant to be de novo. The p.Arg67Ter variant in ZC4H2 has been previously reported in two individuals with Wieacker-Wolff syndrome (PMID: 31206972; PMID: 31885220). This variant was found to be de novo in two individuals with confirmed paternity and maternity (PMID: 31206972; PMID: 31885220). This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 429826) and has been interpreted as pathogenic by GeneDx, Fulgent Genetics, and Ambry Genetics and as likely pathogenic by Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics and Mendelics. In vitro functional studies provide some evidence that the p.Arg67Ter variant may impact protein function (PMID: 31885220). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 67, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the ZC4H2 gene is an established disease mechanism in female-restricted Wieacker-Wolff syndrome. In summary, this variant meets criteria to be classified as pathogenic for female-restricted Wieacker-Wolff syndrome. ACMG/AMP Criteria applied: PVS1, PS2, PS3_Supporting, PS4_Supporting, PM2_Supporting (Richards 2015). -

Wieacker-Wolff syndrome Pathogenic:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Apr 13, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: a truncated protein with altered subcellular localization (Wang et al., 2020); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31349857, 31885220, 33949289, 36250278, 31206972) -

Inborn genetic diseases Pathogenic:1

Sep 06, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.56
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs1131691616; hg19: chrX-64141723;