rs1554081108

Positions:

• chr5-150398364-CAA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.98

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]

ACMG classification

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	Protein	UniProt
TCOF1	NM_001371623.1	c.4358_4359del	p.Lys1453ArgfsTer18	frameshift_variant	25/27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2	c.4358_4359del	p.Lys1453ArgfsTer18	frameshift_variant	25/27		NM_001371623.1	ENSP00000493815	P3

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

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 11, 2017

The 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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 19, 2018

This 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

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

Other links and lift over

dbSNP: rs1554081108; hg19: chr5-149777927;