rs1057520297

Variant names:

• chrX-64921845-A-T
• rs1057520297
• NM_018684.4:c.197T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_018684.4(ZC4H2):​c.197T>A​(p.Leu66His) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L66F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 21)
• Consequence: ZC4H2 NM_018684.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.01
• Publications: 3 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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-64921846-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3781335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant X-64921845-A-T is Pathogenic according to our data. Variant chrX-64921845-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 378042.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC4H2	NM_018684.4	c.197T>A	p.Leu66His	missense_variant	Exon 2 of 5	ENST00000374839.8	NP_061154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC4H2	ENST00000374839.8	c.197T>A	p.Leu66His	missense_variant	Exon 2 of 5	1	NM_018684.4	ENSP00000363972.3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Wieacker-Wolff syndrome Pathogenic:1

Mar 02, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	.;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.6	M;M;.
PhyloP100		9.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.96
MutPred		0.83		Loss of stability (P = 0.0086);Loss of stability (P = 0.0086);.;
MVP		0.96
MPC		2.2
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.97
Mutation Taster		=6/94	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: rs1057520297; hg19: chrX-64141725;