X-64917821-G-A

Position:

• chrX-64917821-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_Moderate PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_018684.4(ZC4H2):​c.637C>T​(p.Arg213Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZC4H2 NM_018684.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.40

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 17 ACMG points.

• PS1: Transcript NM_018684.4 (ZC4H2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 4 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-64917820-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1691760.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant X-64917821-G-A is Pathogenic according to our data. Variant chrX-64917821-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 50983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-64917821-G-A is described in Lovd as [Pathogenic]. Variant chrX-64917821-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC4H2	NM_018684.4	c.637C>T	p.Arg213Trp	missense_variant	5/5	ENST00000374839.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC4H2	ENST00000374839.8	c.637C>T	p.Arg213Trp	missense_variant	5/5	1	NM_018684.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2021	Not observed at significant frequency 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: 23623388, 26056227, 28345801, 29150902, 33504798, 33739554, 31206972) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2017	This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change is unable to rescue the phenotype in a zebrafish knockout model (PMID: 26056227). This variant has been reported to segregate with disease in two families affected with arthrogryposis multiplex congenita and intellectual disability (PMID: 23623388) and another family affected with intellectual disability, contractures, and spasticity (PMID: 26056227). ClinVar contains an entry for this variant (Variation ID: 50983). This sequence change replaces arginine with tryptophan at codon 213 of the ZC4H2 protein (p.Arg213Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2022

The c.637C>T (p.R213W) alteration is located in exon 5 (coding exon 5) of the ZC4H2 gene. This alteration results from a C to T substitution at nucleotide position 637, causing the arginine (R) at amino acid position 213 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant co-segregated in multiple families in individuals with ZC4H2-related disorder (Hirata, 2013; May, 2015). This variant has been determined to be the result of a de novo mutation in an individual with ZC4H2-related disorder (Frints, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to disrupt the nuclear localization signal motif (Ambry internal data; Hirata, 2013; May, 2015) and has been determined to impact protein function (Hirata, 2013; May, 2015; Ma, 2017) This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Wieacker-Wolff syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 02, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.63
MutPred		0.49		Loss of solvent accessibility (P = 0.0036);.;
MVP		0.96
MPC		3.1
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.89
gMVP		0.79

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: rs879255236; hg19: chrX-64137701;