X-64917841-C-A

Variant names:

• chrX-64917841-C-A
• rs1064795753
• NM_018684.4:c.617G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP5_Moderate BP4

The NM_018684.4(ZC4H2):​c.617G>T​(p.Cys206Phe) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C206R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZC4H2 NM_018684.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• 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

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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-64917842-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3899255.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant X-64917841-C-A is Pathogenic according to our data. Variant chrX-64917841-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 422398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-64917841-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.29977387). . 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.617G>T	p.Cys206Phe	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.617G>T	p.Cys206Phe	missense_variant	Exon 5 of 5	1	NM_018684.4	ENSP00000363972.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Wieacker-Wolff syndrome, female-restricted Pathogenic:1

Apr 09, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 05, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The C206F variant in the ZC4H2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The C206F variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C206F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, some splice predictor models predict that c.617 G>T (aka C206F) may increase the strength of an existing splice acceptor site in intron 4 that is downstream of the natural splice acceptor site, which may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of c.617 G>T in this individual is unknown. The C206F variant is a strong candidate for a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.023	T
PhyloP100		7.3
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.15
Sift	Benign	0.46	T
Sift4G	Benign	0.62	T
Vest4		0.31
MutPred		0.59		Gain of disorder (P = 0.0413);
MVP		0.75
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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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Other links and lift over

dbSNP: rs1064795753; hg19: chrX-64137721;