ZC4H2 p.Val63Leu

Variant names:

• chrX-64921855-C-A
• NM_018684.4:c.187G>T
• ZC4H2 p.Val63Leu

Your query was ambiguous. Multiple possible variants found:

• chrX-64921855-C-A
• chrX-64921855-C-G
• chrX-64921853-CAC-TAA
• chrX-64921853-CAC-AAG
• chrX-64921853-CAC-GAG
• chrX-64921853-CAC-TAG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM1 PM2 PP3_Moderate

The NM_018684.4(ZC4H2):​c.187G>T​(p.Val63Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V63M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZC4H2 NM_018684.4 missense
• 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: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_018684.4 (ZC4H2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_018684.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

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.187G>T	p.Val63Leu	missense	Exon 2 of 5	NP_061154.1	Q9NQZ6-1
	ZC4H2	NM_001178032.3		c.118G>T	p.Val40Leu	missense	Exon 2 of 5	NP_001171503.1	Q9NQZ6-3
	ZC4H2	NM_001243804.2		c.118G>T	p.Val40Leu	missense	Exon 2 of 5	NP_001230733.1	Q9NQZ6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC4H2	ENST00000374839.8	TSL:1 MANE Select	c.187G>T	p.Val63Leu	missense	Exon 2 of 5	ENSP00000363972.3	Q9NQZ6-1
	ZC4H2	ENST00000337990.2	TSL:2	c.118G>T	p.Val40Leu	missense	Exon 2 of 5	ENSP00000338650.2	Q9NQZ6-3
	ZC4H2	ENST00000447788.6	TSL:2	c.187G>T	p.Val63Leu	missense	Exon 2 of 4	ENSP00000399126.2	Q9NQZ6-4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.85
gMVP		0.84
Mutation Taster		=3/97	disease causing

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

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

Other links and lift over

hg19: chrX-64141735;