Genetic Variant NM_018684.4:c.627G>C (chrX-64917831-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_018684.4(ZC4H2):c.627G>C(p.Lys209Asn) variant causes a missense change involving the alteration of a non-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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K209R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Consequence

ZC4H2
NM_018684.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.14

Publications

2 publications found

Variant links:

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

ZC4H2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 9 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

PP5

Variant X-64917831-C-G is Pathogenic according to our data. Variant chrX-64917831-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1059458.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZC4H2	NM_018684.4	MANE Select	c.627G>C	p.Lys209Asn	missense	Exon 5 of 5	NP_061154.1	Q9NQZ6-1
ZC4H2	NM_001178032.3		c.558G>C	p.Lys186Asn	missense	Exon 5 of 5	NP_001171503.1	Q9NQZ6-3
ZC4H2	NM_001243804.2		c.558G>C	p.Lys186Asn	missense	Exon 5 of 5	NP_001230733.1	Q9NQZ6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZC4H2	ENST00000374839.8	TSL:1 MANE Select	c.627G>C	p.Lys209Asn	missense	Exon 5 of 5	ENSP00000363972.3	Q9NQZ6-1
ZC4H2	ENST00000337990.2	TSL:2	c.558G>C	p.Lys186Asn	missense	Exon 5 of 5	ENSP00000338650.2	Q9NQZ6-3
ZC4H2	ENST00000447788.6	TSL:2	c.464G>C	p.Arg155Thr	missense	Exon 4 of 4	ENSP00000399126.2	Q9NQZ6-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-1.1

PhyloP100

1.1

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.83

MutPred

0.50

Loss of methylation at K209 (P = 0.0111)

MVP

0.76

MPC

3.3

ClinPred

1.0

GERP RS

2.6

Varity_R

0.93

gMVP

0.82

Mutation Taster

=1/99

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over