rs587776585

chr5-150398368-GAAAAA-Gchr5-150398368-GAAAAA-GAAAchr5-150398368-GAAAAA-GAAAAchr5-150398368-GAAAAA-GAAAAAA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001371623.1(TCOF1):c.4364_4368del(p.Lys1455ArgfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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, single submitter P:1
• Conservation: PhyloP100: 2.30

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-150398368-GAAAAA-G is Pathogenic according to our data. Variant chr5-150398368-GAAAAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 660987.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-150398368-GAAAAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.4364_4368del	p.Lys1455ArgfsTer15	frameshift_variant	25/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.4364_4368del	p.Lys1455ArgfsTer15	frameshift_variant	25/27		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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Treacher Collins syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2018

Loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 8894686, 22317976). This variant has been observed in several individuals affected with Treacher-Collins syndrome (TCS) (PMID: 9042910, 20003452, 12114482, Invitae). This variant is also known as nt4130 del(AAAAA) and c.4130-4134delAAAAA in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys1454Argfs*15) in the TCOF1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776585; hg19: chr5-149777931;