X-64921988-CC-TT

Variant names:

• chrX-64921988-CC-TT
• NM_018684.4:c.54-1_54delGGinsAA
• ZC4H2 p.19

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_018684.4(ZC4H2):​c.54-1_54delGGinsAA​(p.19) variant causes a splice acceptor, splice region, synonymous, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R18R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: ZC4H2 NM_018684.4 splice_acceptor, splice_region, synonymous, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Wieacker-Wolff syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Wieacker-Wolff syndrome, female-restricted

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics, G2P
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018684.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC4H2	NM_018684.4	MANE Select	c.54-1_54delGGinsAA	p.19	splice_acceptor splice_region synonymous intron	N/A	NP_061154.1	Q9NQZ6-1
	ZC4H2	NM_001243804.2		c.-16-1_-16delGGinsAA		splice_region	Exon 2 of 5	NP_001230733.1	Q9NQZ6-3
	ZC4H2	NM_001178032.3		c.-17_-16delGGinsAA		5_prime_UTR	Exon 2 of 5	NP_001171503.1	Q9NQZ6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC4H2	ENST00000374839.8	TSL:1 MANE Select	c.54-1_54delGGinsAA	p.19	splice_acceptor splice_region synonymous intron	N/A	ENSP00000363972.3	Q9NQZ6-1
	ZC4H2	ENST00000337990.2	TSL:2	c.-17_-16delGGinsAA		5_prime_UTR	Exon 2 of 5	ENSP00000338650.2	Q9NQZ6-3
	ZC4H2	ENST00000476032.2	TSL:3	c.-17_-16delGGinsAA		5_prime_UTR	Exon 2 of 5	ENSP00000515193.1	A0A8V8TR70

Frequencies

GnomAD3 genomes Cov.: 21

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-64141868;