5-150398372-AAAAAG-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001371623.1(TCOF1):c.4372_4376delAAGAA(p.Lys1458GlufsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,412 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
TCOF1
NM_001371623.1 frameshift
NM_001371623.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.22
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 5-150398372-AAAAAG-A is Pathogenic according to our data. Variant chr5-150398372-AAAAAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 3963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150398372-AAAAAG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TCOF1 | NM_001371623.1 | c.4372_4376delAAGAA | p.Lys1458GlufsTer12 | frameshift_variant | Exon 25 of 27 | ENST00000643257.2 | NP_001358552.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248180Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134486
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461412Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727044
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Treacher Collins syndrome 1 Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 31, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 16, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Autoinflammatory diseases unit, CHU de Montpellier | Apr 14, 2016 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2000 | - - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003963 / PMID: 9042910). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PVS1+PS4+PS2_Supporting+PP1_Strong+PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2025 | This sequence change creates a premature translational stop signal (p.Lys1457Glufs*12) in the TCOF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 8894686, 22317976). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Treacher Collins syndrome (PMID: 9042910, 11013442, 20003452, 21951868, 22317976). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2023 | Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 32 amino acids are lost and replaced with 11 incorrect amino acids (HGMD); This variant is associated with the following publications: (PMID: 28927774, 9042910, 27895973, 21951868, 11013442, 29230583, 20003452, 22317976, 31107123, 32351010, 30577886, 32909271, 33105617, 33332773, 34397304, 34714179, 37640998) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2018 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 19, 2021 | The c.4369_4373delAAGAA (p.K1457Efs*12) alteration, located in exon 25 (coding exon 25) of the TCOF1 gene, consists of a deletion of 5 nucleotides from position 4369 to 4373, causing a translational frameshift with a predicted alternate stop codon after 12 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in multiple unrelated patients with Treacher Collins syndrome (Vincent, 2016; Kantaputra, 2020, Pan, 2020). In a 3-generation family with four individuals affected with Treacher Collins, the patients did not have the typical facial gestalt and had milder facial features; however, lateral cephalometric analyses identified short anterior and posterior cranial bases and hypoplastic maxilla and mandible. Computed tomography showed fusion of malleus and incus, sclerotic mastoid, hypoplastic middle ear space with a soft tissue remnant, dehiscence of facial nerve, and monopodial stapes (Kantaputra, 2020). The authors suggest that the absence of a common facial phenotype and/or the presence of monopodial stapes may be the effects of this specific TCOF1 mutation. Based on the available evidence, this alteration is classified as pathogenic. - |
Treacher Collins syndrome Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at