chrX-64921812-C-T

Position:

• chrX-64921812-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_018684.4(ZC4H2):​c.225+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZC4H2 NM_018684.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.08

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]

ZC4H2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 4: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai [when BayesDel_noAF was below the threshold]
• PP5: Variant X-64921812-C-T is Pathogenic according to our data. Variant chrX-64921812-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 378044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC4H2	NM_018684.4	c.225+5G>A		splice_region_variant, intron_variant		ENST00000374839.8	NP_061154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC4H2	ENST00000374839.8	c.225+5G>A		splice_region_variant, intron_variant		1	NM_018684.4	ENSP00000363972.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 03, 2023	This variant has been observed in individual(s) with clinical features of X-linked intellectual disability (PMID: 26056227, 36250278; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in intron 2 (PMID: 26056227). ClinVar contains an entry for this variant (Variation ID: 378044). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the ZC4H2 gene. It does not directly change the encoded amino acid sequence of the ZC4H2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 15 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2021	Canonical splice site variant predicted to result in an in-frame insertion of 15 amino acids of exon 2 (May et al., 2015); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26056227, 28345801, 29150902, 17576681, 9536098, 32860008, 31885220) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ZC4H2: PP1:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting -

Wieacker-Wolff syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 02, 2017

- -

ZC4H2-related X-linked intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 02, 2021

The ZC4H2 c.225+5G>A variant is an intronic splice region variant that has been reported in two studies, in which it is found in a hemizygous state in a total of four individuals from two unrelated families with ZC4H2-related X-linked intellectual disability, including one family with three affected male individuals (May et al. 2015; Bertoli-Avella et al. 2021). The c.225+5G>A variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database despite its location in a region of reasonably good sequence coverage, which suggests the variant is rare. May et al. (2015) demonstrated that the variant resulted in an in-frame insertion of 15 amino acids, and RT-PCR confirmed the absence of a wild type transcript. This variant was identified in a de novo state. Based on the available evidence, the c.225+5G>A variant is classified as likely pathogenic for ZC4H2-related X-linked intellectual disability. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	35
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.85		Position offset: -40

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057520298; hg19: chrX-64141692; COSMIC: COSV62006293; COSMIC: COSV62006293;