chrX-64917843-A-T

Position:

chrX-64917843-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001178033.3(ZC4H2):c.452T>A(p.Phe151Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,208,636 control chromosomes in the GnomAD database, including 1,907 homozygotes. There are 4,972 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 1029 hom., 2371 hem., cov: 22)

Exomes 𝑓: 0.0087 ( 878 hom. 2601 hem. )

Consequence

ZC4H2
NM_001178033.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0390

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 links:

ZC4H2 (HGNC:):

ZC4H2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Zinc finger C4H2 domain-containing protein (size 223) in uniprot entity ZC4H2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001178033.3

BP4

Computational evidence support a benign effect (MetaRNN=0.004156381).

BP6

Variant X-64917843-A-T is Benign according to our data. Variant chrX-64917843-A-T is described in ClinVar as [Benign]. Clinvar id is 587843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC4H2	NM_018684.4 linkuse as main transcript	c.615T>A	p.Leu205Leu	synonymous_variant	5/5	ENST00000374839.8	NP_061154.1	Q9NQZ6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC4H2	ENST00000374839.8 linkuse as main transcript	c.615T>A	p.Leu205Leu	synonymous_variant	5/5	1	NM_018684.4	ENSP00000363972.3		Q9NQZ6-1

Frequencies

GnomAD3 genomes

AF:

0.0822

AC:

9117

AN:

110934

Hom.:

1030

Cov.:

AF XY:

0.0710

AC XY:

2356

AN XY:

33180

show subpopulations

Gnomad AFR

AF:

0.289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0258

Gnomad ASJ

AF:

0.000759

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000770

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00424

Gnomad NFE

AF:

0.000565

Gnomad OTH

AF:

0.0577

GnomAD3 exomes

AF:

0.0239

AC:

4339

AN:

181710

Hom.:

447

AF XY:

0.0154

AC XY:

1020

AN XY:

66258

show subpopulations

Gnomad AFR exome

AF:

0.300

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.000536

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000321

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000518

Gnomad OTH exome

AF:

0.0100

GnomAD4 exome

AF:

0.00866

AC:

9501

AN:

1097648

Hom.:

878

Cov.:

AF XY:

0.00716

AC XY:

2601

AN XY:

363028

show subpopulations

Gnomad4 AFR exome

AF:

0.296

Gnomad4 AMR exome

AF:

0.0148

Gnomad4 ASJ exome

AF:

0.000568

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000815

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000238

Gnomad4 OTH exome

AF:

0.0191

GnomAD4 genome

AF:

0.0822

AC:

9128

AN:

110988

Hom.:

1029

Cov.:

AF XY:

0.0713

AC XY:

2371

AN XY:

33244

show subpopulations

Gnomad4 AFR

AF:

0.288

Gnomad4 AMR

AF:

0.0257

Gnomad4 ASJ

AF:

0.000759

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000772

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000566

Gnomad4 OTH

AF:

0.0570

Alfa

AF:

0.0147

Hom.:

376

Bravo

AF:

0.0948

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.290

AC:

1113

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.0270

AC:

3276

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

5.8

DANN

Benign

0.78

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

P;P;P;P

PROVEAN

Benign

-0.090

REVEL

Benign

0.060

Sift

Benign

0.23

Sift4G

Benign

0.63

Vest4

0.17

ClinPred

0.0074

GERP RS

0.79

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over