rs1929002470

Variant names:

• chrX-64917808-T-C
• rs1929002470
• NM_018684.4:c.650A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_018684.4(ZC4H2):​c.650A>G​(p.Lys217Arg) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZC4H2 NM_018684.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.40
• 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: 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_018684.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-64917808-T-C is Pathogenic according to our data. Variant chrX-64917808-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 834097.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3894233). . 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.650A>G	p.Lys217Arg	missense	Exon 5 of 5	NP_061154.1	Q9NQZ6-1
	ZC4H2	NM_001178032.3		c.581A>G	p.Lys194Arg	missense	Exon 5 of 5	NP_001171503.1	Q9NQZ6-3
	ZC4H2	NM_001243804.2		c.581A>G	p.Lys194Arg	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.650A>G	p.Lys217Arg	missense	Exon 5 of 5	ENSP00000363972.3	Q9NQZ6-1
	ZC4H2	ENST00000337990.2	TSL:2	c.581A>G	p.Lys194Arg	missense	Exon 5 of 5	ENSP00000338650.2	Q9NQZ6-3
	ZC4H2	ENST00000447788.6	TSL:2	c.487A>G	p.Ser163Gly	missense	Exon 4 of 4	ENSP00000399126.2	Q9NQZ6-4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Wieacker-Wolff syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.97	T
PhyloP100		7.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.47
MutPred		0.44		Loss of methylation at K217 (P = 0.007)
MVP		0.81
MPC		2.6
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.75
gMVP		0.50
Mutation Taster		=3/97	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: rs1929002470; hg19: chrX-64137688;