rs398122939

Positions:

• chrX-64917857-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_018684.4(ZC4H2):​c.601C>T​(p.Pro201Ser) 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 pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely 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. P201H) 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: 9.22

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 12 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 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant X-64917857-G-A is Pathogenic according to our data. Variant chrX-64917857-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50982.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-64917857-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC4H2	NM_018684.4	c.601C>T	p.Pro201Ser	missense_variant	5/5	ENST00000374839.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC4H2	ENST00000374839.8	c.601C>T	p.Pro201Ser	missense_variant	5/5	1	NM_018684.4	P1

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 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 02, 2013

- -

Neurodevelopmental disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Jun 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	-0.017	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.57		Gain of MoRF binding (P = 0.0359);.;
MVP		0.92
MPC		3.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.72

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: rs398122939; hg19: chrX-64137737;