X-64919176-G-T

Position:

• chrX-64919176-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_018684.4(ZC4H2):​c.427C>A​(p.Gln143Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,791 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
• Consequence: ZC4H2 NM_018684.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.66

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a chain Zinc finger C4H2 domain-containing protein (size 223) in uniprot entity ZC4H2_HUMAN there are 25 pathogenic changes around while only 7 benign (78%) in NM_018684.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3185876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC4H2	NM_018684.4	c.427C>A	p.Gln143Lys	missense_variant	4/5	ENST00000374839.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC4H2	ENST00000374839.8	c.427C>A	p.Gln143Lys	missense_variant	4/5	1	NM_018684.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111791 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33981

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000949

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111791 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33981

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000949

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.35	N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.21
Sift	Benign	0.30	T;T
Sift4G	Benign	0.96	T;T
Polyphen		0.88	P;.
Vest4		0.58
MutPred		0.48		Gain of methylation at Q143 (P = 0.0033);.;
MVP		0.54
MPC		0.0020
ClinPred		0.53	D
GERP RS		5.4
Varity_R		0.60
gMVP		0.68

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: rs1260869746; hg19: chrX-64139056; COSMIC: COSV62005775;