rs1057517668
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_003412.4(ZIC1):c.1165C>T(p.Gln389Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
ZIC1
NM_003412.4 stop_gained
NM_003412.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.47
Genes affected
ZIC1 (HGNC:12872): (Zic family member 1) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. Members of this family are important during development. Aberrant expression of this gene is seen in medulloblastoma, a childhood brain tumor. This gene is closely linked to the gene encoding zinc finger protein of the cerebellum 4, a related family member on chromosome 3. This gene encodes a transcription factor that can bind and transactivate the apolipoprotein E gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-147413372-C-T is Pathogenic according to our data. Variant chr3-147413372-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 372162.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-147413372-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ZIC1 | NM_003412.4 | c.1165C>T | p.Gln389Ter | stop_gained | 3/3 | ENST00000282928.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZIC1 | ENST00000282928.5 | c.1165C>T | p.Gln389Ter | stop_gained | 3/3 | 1 | NM_003412.4 | P1 | |
ZIC1 | ENST00000488404.5 | c.232C>T | p.Gln78Ter | stop_gained | 3/3 | 5 | |||
ZIC1 | ENST00000472523.1 | n.521+19430C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Structural brain anomalies with impaired intellectual development and craniosynostosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 14, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2018 | The Q389X variant in the ZIC1 gene has been reported previously in an individual with craniosynostosis, intellectual disability, and additional cerebral anomalies (Twigg et al., 2015). Functional studies in Xenopus embryos suggest that Q389X is damaging to embryonic development (Twigg et al., 2015). This variant is predicted to cause loss of normal protein function through protein truncation as the last 59 amino acids of the ZIC1 protein are lost. The Q389X variant is not observed in large population cohorts (Lek et al., 2016). Additionally, the Q389X variant has occurred de novo in this individual whose reported clinical presentation is consistent with a ZIC1-related disorder. We interpret Q389X as a pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at