chr5-150357855-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1PM2PP3_StrongPP5

The NM_001371623.1(TCOF1):​c.108+1G>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

TCOF1
NM_001371623.1 splice_donor

Scores

3
3
1
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.63
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 15 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 5-150357855-G-A is Pathogenic according to our data. Variant chr5-150357855-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3061355.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TCOF1NM_001371623.1 linkuse as main transcriptc.108+1G>A splice_donor_variant ENST00000643257.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TCOF1ENST00000643257.2 linkuse as main transcriptc.108+1G>A splice_donor_variant NM_001371623.1 P3Q13428-3

Frequencies

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

ClinVar

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

Submissions by phenotype

TCOF1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 16, 2024The TCOF1 c.108+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in TCOF1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.80
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.23
Position offset: -40
DS_DL_spliceai
0.99
Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-149737418; API