rs1554138819
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001371623.1(TCOF1):c.2796_2797del(p.Gly933GlufsTer9) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
TCOF1
NM_001371623.1 frameshift
NM_001371623.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.47
Genes affected
TCOF1 (HGNC:11654): (treacle ribosome biogenesis factor 1) This gene encodes a nucleolar protein with a LIS1 homology domain. The protein is involved in ribosomal DNA gene transcription through its interaction with upstream binding factor (UBF). Mutations in this gene have been associated with Treacher Collins syndrome, a disorder which includes abnormal craniofacial development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-150379668-CAG-C is Pathogenic according to our data. Variant chr5-150379668-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 477617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150379668-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TCOF1 | NM_001371623.1 | c.2796_2797del | p.Gly933GlufsTer9 | frameshift_variant | 17/27 | ENST00000643257.2 | NP_001358552.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TCOF1 | ENST00000643257.2 | c.2796_2797del | p.Gly933GlufsTer9 | frameshift_variant | 17/27 | NM_001371623.1 | ENSP00000493815 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Treacher Collins syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Aug 12, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 27, 2019 | This variant has been reported in a family affected with Treacher Collins syndrome (PMID: 9096354). This variant is also known as 2565delAG in the literature. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 22317976, 8894686). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly933Glufs*9) in the TCOF1 gene. It is expected to result in an absent or disrupted protein product. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9096354) - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at