X-64917865-C-T

Variant names:

• chrX-64917865-C-T
• rs879255235
• NM_018684.4:c.593G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_018684.4(ZC4H2):​c.593G>A​(p.Arg198Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R198W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZC4H2 NM_018684.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.30

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 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_018684.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-64917866-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant X-64917865-C-T is Pathogenic according to our data. Variant chrX-64917865-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 50981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-64917865-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-64917865-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.42216164). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC4H2	NM_018684.4	c.593G>A	p.Arg198Gln	missense_variant	Exon 5 of 5	ENST00000374839.8	NP_061154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC4H2	ENST00000374839.8	c.593G>A	p.Arg198Gln	missense_variant	Exon 5 of 5	1	NM_018684.4	ENSP00000363972.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wieacker-Wolff syndrome Pathogenic:3

May 02, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 31, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 moderate, PP1 strong -

May 27, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28814648, 31206972, 28345801, 23623388, 31885220, 34322088) -

Wieacker-Wolff syndrome, female-restricted Pathogenic:1

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:23623388, 28814648). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000050981). A different missense change at the same codon (p.Arg198Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000432364). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	31
DANN	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	-0.059	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.15
Sift	Benign	0.034	D
Sift4G	Uncertain	0.034	D
Vest4		0.34
MutPred		0.65		Gain of MoRF binding (P = 0.0081);
MVP		0.54
ClinPred		1.0	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879255235; hg19: chrX-64137745; COSMIC: COSV62004720;