rs113299143

Positions:

chr5-150374956-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001371623.1(TCOF1):c.1281G>A(p.Ala427=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,612,508 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 34)

Exomes 𝑓: 0.0036 ( 23 hom. )

Consequence

TCOF1
NM_001371623.1 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.45

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]

TCOF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 5-150374956-G-A is Benign according to our data. Variant chr5-150374956-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 209027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150374956-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.45 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00283 (427/150692) while in subpopulation NFE AF= 0.00426 (288/67680). AF 95% confidence interval is 0.00385. There are 2 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 427 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1 linkuse as main transcript	c.1281G>A	p.Ala427=	splice_region_variant, synonymous_variant	10/27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2 linkuse as main transcript	c.1281G>A	p.Ala427=	splice_region_variant, synonymous_variant	10/27		NM_001371623.1	ENSP00000493815	P3	Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

427

AN:

150582

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00331

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00183

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00425

Gnomad OTH

AF:

0.00678

GnomAD3 exomes

AF:

0.00279

AC:

695

AN:

248804

Hom.:

AF XY:

0.00277

AC XY:

375

AN XY:

135172

show subpopulations

Gnomad AFR exome

AF:

0.000965

Gnomad AMR exome

AF:

0.00310

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00254

Gnomad NFE exome

AF:

0.00413

Gnomad OTH exome

AF:

0.00412

GnomAD4 exome

AF:

0.00358

AC:

5226

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00341

AC XY:

2482

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00277

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00240

Gnomad4 NFE exome

AF:

0.00425

Gnomad4 OTH exome

AF:

0.00262

GnomAD4 genome

AF:

0.00283

AC:

427

AN:

150692

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

185

AN XY:

73578

show subpopulations

Gnomad4 AFR

AF:

0.00115

Gnomad4 AMR

AF:

0.00331

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00183

Gnomad4 NFE

AF:

0.00426

Gnomad4 OTH

AF:

0.00670

Alfa

AF:

0.00356

Hom.:

Bravo

AF:

0.00300

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TCOF1: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Treacher Collins syndrome 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, no assertion criteria provided	not provided	Genetics Laboratories, Oxford Radcliffe Hospitals NHS Trust	-	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 28, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 25, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 10, 2015	- -

TCOF1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.68

DANN

Benign

0.62

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over