X-64917842-A-G

Variant names:

• chrX-64917842-A-G
• NM_018684.4:c.616T>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_018684.4(ZC4H2):​c.616T>C​(p.Cys206Arg) 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. 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. C206F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZC4H2 NM_018684.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.60

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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 chrX-64917841-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 422398.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant X-64917842-A-G is Pathogenic according to our data. Variant chrX-64917842-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3899255.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.616T>C	p.Cys206Arg	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.616T>C	p.Cys206Arg	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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	-0.10	T
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.65		Gain of MoRF binding (P = 0.0128);.;
MVP		0.96
MPC		4.9
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-64137722;