rs587776584

Variant names:

• chr5-150367911-AGCCAAGGTGAGTGGGACT-A
• rs587776584
• NM_001371623.1:c.376_378+15delAAGGTGAGTGGGACTGCC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001371623.1(TCOF1):​c.376_378+15delAAGGTGAGTGGGACTGCC​(p.Lys126del) variant causes a splice donor, conservative inframe deletion, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCOF1 NM_001371623.1 splice_donor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.72
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae)
• Treacher-Collins syndrome

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.4, offset of 25, new splice context is: aagGTgcct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 5-150367911-AGCCAAGGTGAGTGGGACT-A is Pathogenic according to our data. Variant chr5-150367911-AGCCAAGGTGAGTGGGACT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3967.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	NM_001371623.1	MANE Select	c.376_378+15delAAGGTGAGTGGGACTGCC	p.Lys126del	splice_donor conservative_inframe_deletion splice_region intron	Exon 4 of 27	NP_001358552.1	Q13428-3
	TCOF1	NM_001135243.2		c.376_378+15delAAGGTGAGTGGGACTGCC	p.Lys126del	splice_donor conservative_inframe_deletion splice_region intron	Exon 4 of 27	NP_001128715.1	Q13428-1
	TCOF1	NM_001135244.2		c.376_378+15delAAGGTGAGTGGGACTGCC	p.Lys126del	splice_donor conservative_inframe_deletion splice_region intron	Exon 4 of 26	NP_001128716.1	Q13428-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.376_378+15delAAGGTGAGTGGGACTGCC	p.Lys126del	splice_donor conservative_inframe_deletion splice_region intron	Exon 4 of 27	ENSP00000493815.1	Q13428-3
	TCOF1	ENST00000504761.6	TSL:1	c.376_378+15delAAGGTGAGTGGGACTGCC	p.Lys126del	splice_donor conservative_inframe_deletion splice_region intron	Exon 4 of 26	ENSP00000421655.2	Q13428-1
	TCOF1	ENST00000323668.11	TSL:1	c.376_378+15delAAGGTGAGTGGGACTGCC	p.Lys126del	splice_donor conservative_inframe_deletion splice_region intron	Exon 4 of 26	ENSP00000325223.6	Q13428-2

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587776584; hg19: chr5-149747474;