X-64917820-C-T

Variant names:

• chrX-64917820-C-T
• rs2147345630
• NM_018684.4:c.638G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_018684.4(ZC4H2):​c.638G>A​(p.Arg213Gln) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZC4H2 NM_018684.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.30
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Wieacker-Wolff syndrome, female-restricted

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

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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-64917821-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 50983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant X-64917820-C-T is Pathogenic according to our data. Variant chrX-64917820-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1691760.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41315806). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC4H2	NM_018684.4	MANE Select	c.638G>A	p.Arg213Gln	missense	Exon 5 of 5	NP_061154.1	Q9NQZ6-1
	ZC4H2	NM_001178032.3		c.569G>A	p.Arg190Gln	missense	Exon 5 of 5	NP_001171503.1	Q9NQZ6-3
	ZC4H2	NM_001243804.2		c.569G>A	p.Arg190Gln	missense	Exon 5 of 5	NP_001230733.1	Q9NQZ6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC4H2	ENST00000374839.8	TSL:1 MANE Select	c.638G>A	p.Arg213Gln	missense	Exon 5 of 5	ENSP00000363972.3	Q9NQZ6-1
	ZC4H2	ENST00000337990.2	TSL:2	c.569G>A	p.Arg190Gln	missense	Exon 5 of 5	ENSP00000338650.2	Q9NQZ6-3
	ZC4H2	ENST00000447788.6	TSL:2	c.475G>A	p.Gly159Arg	missense	Exon 4 of 4	ENSP00000399126.2	Q9NQZ6-4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.082	T
PhyloP100		7.3
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.093
Sift	Benign	0.072	T
Sift4G	Benign	0.69	T
Vest4		0.37
MutPred		0.42		Gain of solvent accessibility (P = 0.0037)
MVP		0.56
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.74
Mutation Taster		=45/55	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

Other links and lift over

dbSNP: rs2147345630; hg19: chrX-64137700;