Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_001323638.2(ZEB1):c.-425A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,224 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
ZEB1 (HGNC:11642): (zinc finger E-box binding homeobox 1) This gene encodes a zinc finger transcription factor. The encoded protein likely plays a role in transcriptional repression of interleukin 2. Mutations in this gene have been associated with posterior polymorphous corneal dystrophy-3 and late-onset Fuchs endothelial corneal dystrophy. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Mar 2010]
Computational evidence support a benign effect (MetaRNN=0.014271468).
BP6
Variant 10-31461211-A-C is Benign according to our data. Variant chr10-31461211-A-C is described in ClinVar as [Benign]. Clinvar id is 12633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Jan 01, 2010
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Jan 06, 2020
Reproductive Health Research and Development, BGI Genomics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: curation
The ZEB1 gene is known as TCF8 in the published literature (PMID: 20036349). TCF8NM_030751.5:c.233A>C in the ZEB1 gene has an allele frequency of 0.052 in African subpopulation in the gnomAD database. 30 homozygous occurrences are observed in the gnomAD database. Since the Fuchs Corneal Dystrophy was reported as Late-Onset, we determined to not apply the number of homozygousity as a strong benign evidence. In addition, Riazuddin et al. reported a patient with Late-Onset Fuchs Corneal Dystrophy barboring p.N78T (PMID: 20036349). These evidence suggest the variant to be classified as benign. ACMG/AMP criteria applied: BA1. -
not specified Benign:1
Oct 28, 2020
H3Africa Consortium
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research
While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.083, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -
ZEB1-related disorder Benign:1
May 25, 2022
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Oct 08, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter