rs1556029841

chrX-137567165-CTACT-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_003413.4(ZIC3):c.476_479del(p.Tyr159CysfsTer63) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 25)
• Consequence: ZIC3 NM_003413.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.08

Genes affected

ZIC3 (HGNC:12874): (Zic family member 3) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. This nuclear protein probably functions as a transcription factor in early stages of left-right body axis formation. Mutations in this gene cause X-linked visceral heterotaxy, which includes congenital heart disease and left-right axis defects in organs. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-137567165-CTACT-C is Pathogenic according to our data. Variant chrX-137567165-CTACT-C is described in ClinVar as [Pathogenic]. Clinvar id is 464967.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4	c.476_479del	p.Tyr159CysfsTer63	frameshift_variant	1/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.476_479del	p.Tyr159CysfsTer63	frameshift_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.476_479del	p.Tyr159CysfsTer63	frameshift_variant	1/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.476_479del	p.Tyr159CysfsTer63	frameshift_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 25

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Heterotaxy, visceral, 1, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 25, 2023

This sequence change creates a premature translational stop signal (p.Tyr159Cysfs*63) in the ZIC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZIC3 are known to be pathogenic (PMID: 24123890). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ZIC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 464967). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1556029841; hg19: chrX-136649324;