chr1-244054357-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_205768.3(ZBTB18):c.583C>T(p.Arg195Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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
ZBTB18
NM_205768.3 stop_gained
NM_205768.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 1.88
Genes affected
ZBTB18 (HGNC:13030): (zinc finger and BTB domain containing 18) This gene encodes a C2H2-type zinc finger protein which acts a transcriptional repressor of genes involved in neuronal development. The encoded protein recognizes a specific sequence motif and recruits components of chromatin to target genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]
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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 is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 47 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-244054357-C-T is Pathogenic according to our data. Variant chr1-244054357-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 417741.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-244054357-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ZBTB18 | NM_205768.3 | c.583C>T | p.Arg195Ter | stop_gained | 2/2 | ENST00000358704.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZBTB18 | ENST00000358704.4 | c.583C>T | p.Arg195Ter | stop_gained | 2/2 | 1 | NM_205768.3 | P4 |
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:4Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Intellectual disability, autosomal dominant 22 Pathogenic:1Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant classified as Likely pathogenic and reported on 04-29-2016 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 05, 2022 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2021 | The c.583C>T (p.R195*) alteration, located in exon 2 (coding exon 2) of the ZBTB18 gene, consists of a C to T substitution at nucleotide position 583. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 195. This alteration occurs at the 3' terminus of the ZBTB18 gene and is not expected to trigger nonsense-mediated mRNA decay; however, premature stop codons are typically deleterious in nature. This alteration and other downstream truncations have been reported as disease causing (Lopes, 2016; Depienne, 2017; DDD Study, 2017). Based on data from the Genome Aggregation Database (gnomAD), the ZBTB18 c.583C>T alteration was not observed, with coverage at this position. This alteration was reported in a 5 year old girl with developmental regression at 8 months, severe intellectual disability, nonverbal, hand stereotypies, intense eye communication, breathing disturbances, screaming spells, and microcephaly (Lopes, 2016). Based on the available evidence, this alteration is classified as pathogenic. - |
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
Uncertain
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