X-64917843-A-T

Position:

• chrX-64917843-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018684.4(ZC4H2):​c.615T>A​(p.Leu205=) variant causes a synonymous 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. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L205L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.082 (1029 hom., 2371 hem., cov: 22)
  • Exomes 𝑓: 0.0087 (878 hom. 2601 hem.)
• Consequence: ZC4H2 NM_018684.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0390

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• 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.
• BP7: Synonymous conserved (PhyloP=-0.039 with no splicing effect.
• 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	UniProt
ZC4H2	NM_018684.4	c.615T>A	p.Leu205=	synonymous_variant	5/5	ENST00000374839.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC4H2	ENST00000374839.8	c.615T>A	p.Leu205=	synonymous_variant	5/5	1	NM_018684.4	P1

Frequencies

GnomAD3 genomes AF: 0.0822 AC: 9117 AN: 110934 Hom.: 1030 Cov.: 22 AF XY: 0.0710 AC XY: 2356 AN XY: 33180

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

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.: 30 AF XY: 0.00716 AC XY: 2601 AN XY: 363028

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.: 22 AF XY: 0.0713 AC XY: 2371 AN XY: 33244

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: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.290 AC: 1113

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.0270 AC: 3276

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.8
DANN	Benign	0.78
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.060
Sift	Benign	0.23	T
Sift4G	Benign	0.63	T
Vest4		0.17
ClinPred		0.0074	T
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

Other links and lift over

dbSNP: rs6653206; hg19: chrX-64137723;