X-137566786-C-CG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_003413.4(ZIC3):​c.97dupG​(p.Ala33GlyfsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 24)

Consequence

ZIC3
NM_003413.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.10
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 27 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-137566786-C-CG is Pathogenic according to our data. Variant chrX-137566786-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3572960.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZIC3NM_003413.4 linkc.97dupG p.Ala33GlyfsTer97 frameshift_variant Exon 1 of 3 ENST00000287538.10 NP_003404.1
ZIC3NM_001330661.1 linkc.97dupG p.Ala33GlyfsTer97 frameshift_variant Exon 1 of 3 NP_001317590.1 O60481-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZIC3ENST00000287538.10 linkc.97dupG p.Ala33GlyfsTer97 frameshift_variant Exon 1 of 3 1 NM_003413.4 ENSP00000287538.5 O60481-1
ZIC3ENST00000370606.3 linkc.97dupG p.Ala33GlyfsTer97 frameshift_variant Exon 1 of 3 5 ENSP00000359638.3 O60481-2

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Heterotaxy, visceral, 1, X-linked Pathogenic:1
Oct 18, 2024
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-136648945; API