NM_018684.4:c.148C>T

Variant names:

• chrX-64921894-G-A
• rs797044863
• NM_018684.4:c.148C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018684.4(ZC4H2):​c.148C>T​(p.Gln50*) variant causes a stop gained 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: ZC4H2 NM_018684.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.66
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Wieacker-Wolff syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Wieacker-Wolff syndrome, female-restricted

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-64921894-G-A is Pathogenic according to our data. Variant chrX-64921894-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208658.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018684.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC4H2	NM_018684.4	MANE Select	c.148C>T	p.Gln50*	stop_gained	Exon 2 of 5	NP_061154.1
	ZC4H2	NM_001178032.3		c.79C>T	p.Gln27*	stop_gained	Exon 2 of 5	NP_001171503.1
	ZC4H2	NM_001243804.2		c.79C>T	p.Gln27*	stop_gained	Exon 2 of 5	NP_001230733.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC4H2	ENST00000374839.8	TSL:1 MANE Select	c.148C>T	p.Gln50*	stop_gained	Exon 2 of 5	ENSP00000363972.3
	ZC4H2	ENST00000337990.2	TSL:2	c.79C>T	p.Gln27*	stop_gained	Exon 2 of 5	ENSP00000338650.2
	ZC4H2	ENST00000447788.6	TSL:2	c.148C>T	p.Gln50*	stop_gained	Exon 2 of 4	ENSP00000399126.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Nov 17, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.7
Vest4		0.52
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044863; hg19: chrX-64141774;