X-64917866-G-T

Variant names:

• chrX-64917866-G-T
• rs137962226
• NM_018684.4:c.592C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_018684.4(ZC4H2):​c.592C>A​(p.Arg198Arg) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,208,193 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 38 hem., cov: 22)
  • Exomes 𝑓: 0.00012 (0 hom. 28 hem.)
• Consequence: ZC4H2 NM_018684.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.22
• Publications: 1 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: 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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant X-64917866-G-T is Benign according to our data. Variant chrX-64917866-G-T is described in ClinVar as Benign. ClinVar VariationId is 707771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00118 (131/111482) while in subpopulation AFR AF = 0.00424 (130/30651). AF 95% confidence interval is 0.00365. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 38 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC4H2	NM_018684.4	MANE Select	c.592C>A	p.Arg198Arg	synonymous	Exon 5 of 5	NP_061154.1	Q9NQZ6-1
	ZC4H2	NM_001178032.3		c.523C>A	p.Arg175Arg	synonymous	Exon 5 of 5	NP_001171503.1	Q9NQZ6-3
	ZC4H2	NM_001243804.2		c.523C>A	p.Arg175Arg	synonymous	Exon 5 of 5	NP_001230733.1	Q9NQZ6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC4H2	ENST00000374839.8	TSL:1 MANE Select	c.592C>A	p.Arg198Arg	synonymous	Exon 5 of 5	ENSP00000363972.3	Q9NQZ6-1
	ZC4H2	ENST00000337990.2	TSL:2	c.523C>A	p.Arg175Arg	synonymous	Exon 5 of 5	ENSP00000338650.2	Q9NQZ6-3
	ZC4H2	ENST00000447788.6	TSL:2	c.429C>A	p.Thr143Thr	synonymous	Exon 4 of 4	ENSP00000399126.2	Q9NQZ6-4

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 131 AN: 111427 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000956

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000323 AC: 58 AN: 179616 AF XY: 0.000140

Gnomad AFR exome AF: 0.00402

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 135 AN: 1096711 Hom.: 0 Cov.: 30 AF XY: 0.0000773 AC XY: 28 AN XY: 362123

African (AFR) AF: 0.00402 AC: 106 AN: 26379

American (AMR) AF: 0.000256 AC: 9 AN: 35104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19344

East Asian (EAS) AF: 0.00 AC: 0 AN: 30149

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53773

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40441

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 841361

Other (OTH) AF: 0.000152 AC: 7 AN: 46033

GnomAD4 genome AF: 0.00118 AC: 131 AN: 111482 Hom.: 0 Cov.: 22 AF XY: 0.00113 AC XY: 38 AN XY: 33678

African (AFR) AF: 0.00424 AC: 130 AN: 30651

American (AMR) AF: 0.0000955 AC: 1 AN: 10473

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00 AC: 0 AN: 2582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6047

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53138

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.00136

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	ZC4H2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.71
PhyloP100		9.2
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs137962226; hg19: chrX-64137746;