X-64917823-G-A

Variant names:

• chrX-64917823-G-A
• NM_018684.4:c.635C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP5_Moderate BP4

The NM_018684.4(ZC4H2):​c.635C>T​(p.Ser212Phe) 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 benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZC4H2 NM_018684.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_018684.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-64917823-G-A is Pathogenic according to our data. Variant chrX-64917823-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3893365.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34779334). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC4H2	NM_018684.4	c.635C>T	p.Ser212Phe	missense_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.635C>T	p.Ser212Phe	missense_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 pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 28, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo hemizygous variant in a fetus with short long bones and tricuspid regurgitation in the published literature (PMID: 36923788); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36923788) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.059	T
PhyloP100		9.2
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.17
Sift	Benign	0.85	T
Sift4G	Benign	0.27	T
Vest4		0.29
MutPred		0.38		Gain of phosphorylation at P158 (P = 0.0164);
MVP		0.69
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
Mutation Taster		=30/70	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-64137703; COSMIC: COSV62004558; COSMIC: COSV62004558;