5-150375484-CAGAG-C

Variant names:

• chr5-150375484-CAGAG-C
• rs587776583
• NM_001371623.1:c.1637_1640delAGAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001371623.1(TCOF1):​c.1637_1640delAGAG​(p.Glu546AlafsTer49) 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TCOF1 NM_001371623.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.26
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Treacher Collins syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Treacher-Collins syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 5-150375484-CAGAG-C is Pathogenic according to our data. Variant chr5-150375484-CAGAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 127080.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371623.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	NM_001371623.1	MANE Select	c.1637_1640delAGAG	p.Glu546AlafsTer49	frameshift	Exon 11 of 27	NP_001358552.1
	TCOF1	NM_001135243.2		c.1637_1640delAGAG	p.Glu546AlafsTer49	frameshift	Exon 11 of 27	NP_001128715.1
	TCOF1	NM_001135244.2		c.1637_1640delAGAG	p.Glu546AlafsTer49	frameshift	Exon 11 of 26	NP_001128716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.1637_1640delAGAG	p.Glu546AlafsTer49	frameshift	Exon 11 of 27	ENSP00000493815.1
	TCOF1	ENST00000504761.6	TSL:1	c.1637_1640delAGAG	p.Glu546AlafsTer49	frameshift	Exon 11 of 26	ENSP00000421655.2
	TCOF1	ENST00000323668.11	TSL:1	c.1406_1409delAGAG	p.Glu469AlafsTer49	frameshift	Exon 10 of 26	ENSP00000325223.6

Frequencies

GnomAD3 genomes Cov.: 34

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

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Treacher Collins syndrome 1 Pathogenic:2

Nov 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 22317976, 8894686). This sequence change deletes 4 nucleotides from exon 11 of the TCOF1 mRNA (c.1637_1640delAGAG), causing a frameshift at codon 546. This creates a premature translational stop signal (p.Glu546Alafs*49) and is expected to result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776583; hg19: chr5-149755047;