rs1554138819

Positions:

• chr5-150379668-CAG-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.2796_2797del​(p.Gly933GlufsTer9) 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:3
• Conservation: PhyloP100: 5.47

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 5-150379668-CAG-C is Pathogenic according to our data. Variant chr5-150379668-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 477617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150379668-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.2796_2797del	p.Gly933GlufsTer9	frameshift_variant	17/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.2796_2797del	p.Gly933GlufsTer9	frameshift_variant	17/27		NM_001371623.1	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

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Treacher Collins syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2019	This variant has been reported in a family affected with Treacher Collins syndrome (PMID: 9096354). This variant is also known as 2565delAG in the literature. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 22317976, 8894686). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly933Glufs*9) in the TCOF1 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 12, 2020	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9096354) -

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: rs1554138819; hg19: chr5-149759231;