X-64917850-C-A

Position:

• chrX-64917850-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP5_Moderate BP4

The NM_018684.4(ZC4H2):​c.608G>T​(p.Cys203Phe) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C203S) has been classified 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: 7.30

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a zinc_finger_region C4H2-type (size 17) in uniprot entity ZC4H2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_018684.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP5: Variant X-64917850-C-A is Pathogenic according to our data. Variant chrX-64917850-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252557.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3994748). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC4H2	NM_018684.4	c.608G>T	p.Cys203Phe	missense_variant	5/5	ENST00000374839.8	NP_061154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC4H2	ENST00000374839.8	c.608G>T	p.Cys203Phe	missense_variant	5/5	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 09, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	-0.023	T
MutationTaster	Benign	1.0	D;D;D;N
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.25
Sift	Benign	0.20	T
Sift4G	Benign	0.13	T
Vest4		0.18
MutPred		0.61		Gain of catalytic residue at M145 (P = 0.0271);
MVP		0.72
ClinPred		1.0	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs879255362; hg19: chrX-64137730;