rs587776582

chr5-150398372-AAAAAG-A

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.4372_4376del(p.Lys1458GlufsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,412 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TCOF1 NM_001371623.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 4.22

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 5-150398372-AAAAAG-A is Pathogenic according to our data. Variant chr5-150398372-AAAAAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 3963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150398372-AAAAAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.4372_4376del	p.Lys1458GlufsTer12	frameshift_variant	25/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.4372_4376del	p.Lys1458GlufsTer12	frameshift_variant	25/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248180 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134486

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461412 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727044

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Treacher Collins syndrome 1 Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2000	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Autoinflammatory diseases unit, CHU de Montpellier	Apr 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 03, 2023	This sequence change creates a premature translational stop signal (p.Lys1457Glufs*12) in the TCOF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 8894686, 22317976). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Treacher Collins syndrome (PMID: 9042910, 11013442, 20003452, 21951868, 22317976). ClinVar contains an entry for this variant (Variation ID: 3963). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003963 / PMID: 9042910). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 31, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2023	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 32 amino acids are lost and replaced with 11 incorrect amino acids (HGMD); This variant is associated with the following publications: (PMID: 28927774, 9042910, 27895973, 21951868, 11013442, 29230583, 20003452, 22317976, 31107123, 32351010, 30577886, 32909271, 33105617, 33332773, 34397304, 34714179, 37640998) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2021

The c.4369_4373delAAGAA (p.K1457Efs*12) alteration, located in exon 25 (coding exon 25) of the TCOF1 gene, consists of a deletion of 5 nucleotides from position 4369 to 4373, causing a translational frameshift with a predicted alternate stop codon after 12 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in multiple unrelated patients with Treacher Collins syndrome (Vincent, 2016; Kantaputra, 2020, Pan, 2020). In a 3-generation family with four individuals affected with Treacher Collins, the patients did not have the typical facial gestalt and had milder facial features; however, lateral cephalometric analyses identified short anterior and posterior cranial bases and hypoplastic maxilla and mandible. Computed tomography showed fusion of malleus and incus, sclerotic mastoid, hypoplastic middle ear space with a soft tissue remnant, dehiscence of facial nerve, and monopodial stapes (Kantaputra, 2020). The authors suggest that the absence of a common facial phenotype and/or the presence of monopodial stapes may be the effects of this specific TCOF1 mutation. Based on the available evidence, this alteration is classified as pathogenic. -

Treacher Collins syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

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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: rs587776582; hg19: chr5-149777935;