Variant 5-150375119-TCAGA-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001371623.1(TCOF1):c.1448_1451del(p.Asp483ValfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)

Consequence

TCOF1
NM_001371623.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.39

Variant links:

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]

TCOF1 links:

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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 5-150375119-TCAGA-T is Pathogenic according to our data. Variant chr5-150375119-TCAGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1 linkuse as main transcript	c.1448_1451del	p.Asp483ValfsTer9	frameshift_variant	10/27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2 linkuse as main transcript	c.1448_1451del	p.Asp483ValfsTer9	frameshift_variant	10/27		NM_001371623.1	ENSP00000493815	P3	Q13428-3

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely 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	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2017	This sequence change creates a premature translational stop signal (p.Asp483Valfs*9) in the TCOF1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TCOF1-related disease. ClinVar contains an entry for this variant (Variation ID: 420429). Loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 8894686, 22317976). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Autoinflammatory diseases unit, CHU de Montpellier	May 16, 2018	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2016

The c.1448_1451delACAG likely pathogenic variant in the TCOF1 gene causes a frameshift starting with codon Aspartic acid 483, changes this amino acid to a Valine residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Asp483ValfsX9. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the c.1448_1451delACAG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although c.1448_1451delACAG has not been previously reported to our knowledge, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing