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rs1554081108

Variant summary

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

The NM_001371623.1(TCOF1):c.4358_4359del(p.Lys1453ArgfsTer18) variant causes a frameshift change. 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: 32)

Consequence

TCOF1
NM_001371623.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.98
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]

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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 5-150398364-CAA-C is Pathogenic according to our data. Variant chr5-150398364-CAA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 503704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150398364-CAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TCOF1NM_001371623.1 linkuse as main transcriptc.4358_4359del p.Lys1453ArgfsTer18 frameshift_variant 25/27 ENST00000643257.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TCOF1ENST00000643257.2 linkuse as main transcriptc.4358_4359del p.Lys1453ArgfsTer18 frameshift_variant 25/27 NM_001371623.1 P3Q13428-3

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxDec 11, 2017The c.4355_4356delAA variant in the TCOF1 gene has been reported previously in at least one individual suspicious for Treacher Collins syndrome (Splendore et al., 2002). This deletion causes a frameshift starting with codon Lysine 1452, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Lys1452ArgfsX18. This variant is predicted to cause loss of normal protein function through protein truncation. Based on currently available evidence, c.4355_4356delAA is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded. -
Treacher Collins syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeMar 19, 2018This sequence change creates a premature translational stop signal (p.Lys1452Argfs*18) 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 been reported in an individual affected with Treacher Collins syndrome (PMID: 12114482). This variant is also known as c.4124-4125delAA in the literature. Loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 8894686, 22317976). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554081108; hg19: chr5-149777927; API