rs1554081112

Positions:

• chr5-150398364-CAAAG-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.4360_4363delGAAA​(p.Glu1454fs) 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
• Clinical Significance: 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-CAAAG-C is Pathogenic according to our data. Variant chr5-150398364-CAAAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 452460.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	c.4360_4363delGAAA	p.Glu1454fs	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.4360_4363delGAAA	p.Glu1454fs	frameshift_variant	25/27		NM_001371623.1	ENSP00000493815.1

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

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2022

Frameshift variant predicted to result in protein truncation, as the last 36 amino acids are replaced with 120 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Treacher Collins syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2017

For these reasons, this variant has been classified as Pathogenic. Many different insertion and deletion variants in this region have been reported in individuals affected with Treacher-Collins syndrome, and therefore is considered to be a mutational hotspot (PMID: 12114482). These include several downstream variants (c.4362_4365delAAAA, c.4365delA, c.4366_4369delGAAA) which result in similar shifts in the read-frame and extension of the TCOF1 protein (PMID: 12114482, 22317976). This suggests that disruption of this region of the TCOF1 protein is causative of disease. This variant has not been reported in the literature in individuals with TCOF1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change deletes 4 nucleotides from exon 25 the TCOF1 gene, causing a frameshift at codon 1453 (p.Glu1453Lysfs*121). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acids of the TCOF1 protein, and to extend the protein by an additional 84 amino acids. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1554081112; hg19: chr5-149777927;