chr5-150357771-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001371623.1(TCOF1):​c.25G>T​(p.Glu9Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TCOF1
NM_001371623.1 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.83
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 159 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-150357771-G-T is Pathogenic according to our data. Variant chr5-150357771-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 938964.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TCOF1NM_001371623.1 linkuse as main transcriptc.25G>T p.Glu9Ter stop_gained 1/27 ENST00000643257.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TCOF1ENST00000643257.2 linkuse as main transcriptc.25G>T p.Glu9Ter stop_gained 1/27 NM_001371623.1 P3Q13428-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Treacher Collins syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 16, 2019This sequence change creates a premature translational stop signal (p.Glu9*) in the TCOF1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TCOF1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 8894686, 22317976). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Uncertain
0.88
D
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A
Vest4
0.71, 0.71, 0.71, 0.66, 0.71, 0.63, 0.63
GERP RS
4.3
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1758946466; hg19: chr5-149737334; API