rs140551642

Variant names:

• chrX-64920062-C-A
• rs140551642
• NM_018684.4:c.398+19G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-64920062-C-A
• chrX-64920062-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018684.4(ZC4H2):​c.398+19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00704 in 1,202,881 control chromosomes in the GnomAD database, including 33 homozygotes. There are 2,712 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 0.0068 (4 hom., 216 hem., cov: 22)
  • Exomes 𝑓: 0.0071 (29 hom. 2496 hem.)
• Consequence: ZC4H2 NM_018684.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.338
• Publications: 0 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-64920062-C-A is Benign according to our data. Variant chrX-64920062-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00676 (751/111031) while in subpopulation NFE AF = 0.00824 (437/53011). AF 95% confidence interval is 0.00761. There are 4 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC4H2	NM_018684.4	c.398+19G>T		intron_variant	Intron 3 of 4	ENST00000374839.8	NP_061154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC4H2	ENST00000374839.8	c.398+19G>T		intron_variant	Intron 3 of 4	1	NM_018684.4	ENSP00000363972.3

Frequencies

GnomAD3 genomes AF: 0.00681 AC: 756 AN: 110980 Hom.: 5 Cov.: 22

Gnomad AFR AF: 0.000591

Gnomad AMI AF: 0.00586

Gnomad AMR AF: 0.00489

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00115

Gnomad FIN AF: 0.0305

Gnomad MID AF: 0.0377

Gnomad NFE AF: 0.00824

Gnomad OTH AF: 0.00675

GnomAD2 exomes AF: 0.00778 AC: 1348 AN: 173246 AF XY: 0.00724

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.00799

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00707 AC: 7722 AN: 1091850 Hom.: 29 Cov.: 29 AF XY: 0.00696 AC XY: 2496 AN XY: 358450

African (AFR) AF: 0.000951 AC: 25 AN: 26298

American (AMR) AF: 0.00307 AC: 107 AN: 34803

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 290 AN: 18896

East Asian (EAS) AF: 0.00 AC: 0 AN: 30133

South Asian (SAS) AF: 0.00125 AC: 66 AN: 52790

European-Finnish (FIN) AF: 0.0319 AC: 1286 AN: 40306

Middle Eastern (MID) AF: 0.0116 AC: 42 AN: 3611

European-Non Finnish (NFE) AF: 0.00666 AC: 5590 AN: 839190

Other (OTH) AF: 0.00690 AC: 316 AN: 45823

GnomAD4 genome AF: 0.00676 AC: 751 AN: 111031 Hom.: 4 Cov.: 22 AF XY: 0.00649 AC XY: 216 AN XY: 33257

African (AFR) AF: 0.000589 AC: 18 AN: 30545

American (AMR) AF: 0.00488 AC: 51 AN: 10442

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 44 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3498

South Asian (SAS) AF: 0.00116 AC: 3 AN: 2589

European-Finnish (FIN) AF: 0.0305 AC: 180 AN: 5908

Middle Eastern (MID) AF: 0.0183 AC: 4 AN: 218

European-Non Finnish (NFE) AF: 0.00824 AC: 437 AN: 53011

Other (OTH) AF: 0.00666 AC: 10 AN: 1501

Alfa AF: 0.0102 Hom.: 75

Bravo AF: 0.00504

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 03, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.0
DANN	Benign	0.36
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs140551642; hg19: chrX-64139942;