Genetic Variant NM_018684.4:c.654G>A (chrX-64917804-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_018684.4(ZC4H2):c.654G>A(p.Pro218Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,209,202 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 163 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00046 ( 0 hom. 161 hem. )

Consequence

ZC4H2
NM_018684.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.237

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029077232).

BP6

Variant X-64917804-C-T is Benign according to our data. Variant chrX-64917804-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 767079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.237 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000206 (23/111609) while in subpopulation NFE AF = 0.000357 (19/53149). AF 95% confidence interval is 0.000234. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

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.654G>A	p.Pro218Pro	synonymous	Exon 5 of 5	NP_061154.1	Q9NQZ6-1
ZC4H2	NM_001178033.3		c.491G>A	p.Arg164Gln	missense	Exon 4 of 4	NP_001171504.1	Q9NQZ6-4
ZC4H2	NM_001178032.3		c.585G>A	p.Pro195Pro	synonymous	Exon 5 of 5	NP_001171503.1	Q9NQZ6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZC4H2	ENST00000374839.8	TSL:1 MANE Select	c.654G>A	p.Pro218Pro	synonymous	Exon 5 of 5	ENSP00000363972.3	Q9NQZ6-1
ZC4H2	ENST00000447788.6	TSL:2	c.491G>A	p.Arg164Gln	missense	Exon 4 of 4	ENSP00000399126.2	Q9NQZ6-4
ZC4H2	ENST00000337990.2	TSL:2	c.585G>A	p.Pro195Pro	synonymous	Exon 5 of 5	ENSP00000338650.2	Q9NQZ6-3

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

111609

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000357

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000199

AC:

AN:

181250

AF XY:

0.000197

show subpopulations

Gnomad AFR exome

AF:

0.000230

Gnomad AMR exome

AF:

0.0000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000383

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.000457

AC:

502

AN:

1097593

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

161

AN XY:

362977

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26390

American (AMR)

AF:

0.0000284

AC:

AN:

35156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19373

East Asian (EAS)

AF:

0.00

AC:

AN:

30178

South Asian (SAS)

AF:

0.0000371

AC:

AN:

53963

European-Finnish (FIN)

AF:

0.0000494

AC:

AN:

40485

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.000561

AC:

472

AN:

841853

Other (OTH)

AF:

0.000456

AC:

AN:

46076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000206

AC:

AN:

111609

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

33789

show subpopulations

African (AFR)

AF:

0.000130

AC:

AN:

30687

American (AMR)

AF:

0.00

AC:

AN:

10480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3548

South Asian (SAS)

AF:

0.00

AC:

AN:

2634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6039

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000357

AC:

AN:

53149

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000303

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000173

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Genetic developmental and epileptic encephalopathy (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.0

(source)

DANN

Benign

0.88

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.44

M_CAP

Benign

0.0020

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.0

PhyloP100

0.24

PROVEAN

Benign

0.12

REVEL

Benign

0.13

Sift

Benign

0.36

Sift4G

Benign

0.39

Vest4

0.15

MVP

0.093

ClinPred

0.016

GERP RS

-11

Mutation Taster

=99/1

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over