X-64917840-G-A

Variant names:

• chrX-64917840-G-A
• NM_018684.4:c.618C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 6P and 6B. PM1 PM2 PM5 BP4_Strong BP6_Moderate

The NM_001178033.3(ZC4H2):​c.455C>T​(p.Ala152Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A152E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZC4H2 NM_001178033.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.10

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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 0 uncertain in NM_001178033.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-64917840-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1189614.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.057846814).
• BP6: Variant X-64917840-G-A is Benign according to our data. Variant chrX-64917840-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3984033.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC4H2	NM_018684.4	c.618C>T	p.Cys206Cys	synonymous_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.618C>T	p.Cys206Cys	synonymous_variant	Exon 5 of 5	1	NM_018684.4	ENSP00000363972.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Jun 07, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	10
DANN	Benign	0.97
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.1
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.074
Sift	Benign	0.21	T
Sift4G	Benign	0.37	T
Vest4		0.17
MutPred		0.54		Loss of helix (P = 0.0138);
MVP		0.28
ClinPred		0.10	T
GERP RS		3.7
Mutation Taster		=47/53	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

Publications

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Other links and lift over

hg19: chrX-64137720;