5-150393480-G-A

Position:

chr5-150393480-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001371623.1(TCOF1):c.3712G>A(p.Ala1238Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,614,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 3 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0190

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:

TCOF1 (HGNC:):

TCOF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045256913).

BP6

Variant 5-150393480-G-A is Benign according to our data. Variant chr5-150393480-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 352232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150393480-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00197 (300/152226) while in subpopulation AFR AF= 0.00578 (240/41530). AF 95% confidence interval is 0.00518. There are 0 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1 linkuse as main transcript	c.3712G>A	p.Ala1238Thr	missense_variant	23/27	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.3712G>A	p.Ala1238Thr	missense_variant	23/27		NM_001371623.1	ENSP00000493815.1		Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

300

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00580

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00136

AC:

342

AN:

251428

Hom.:

AF XY:

0.00116

AC XY:

157

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00584

Gnomad AMR exome

AF:

0.00364

Gnomad ASJ exome

AF:

0.00576

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.000557

AC:

815

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000540

AC XY:

393

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00633

Gnomad4 AMR exome

AF:

0.00358

Gnomad4 ASJ exome

AF:

0.00566

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000166

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00197

AC:

300

AN:

152226

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00578

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000902

Hom.:

Bravo

AF:

0.00239

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00136

AC:

165

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TCOF1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 18, 2017	- -

Treacher Collins syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

- -

TCOF1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

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

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.0

DANN

Benign

0.14

DEOGEN2

Benign

0.058

.;T;.;.;.;.;.;.;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.62

T;T;T;T;.;T;T;T;.;T

MetaRNN

Benign

0.0045

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.9

.;N;.;.;.;.;.;.;N;.

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-2.4

.;N;N;N;.;.;N;N;N;N

REVEL

Benign

0.10

Sift

Uncertain

0.024

.;D;T;T;.;.;T;T;T;T

Sift4G

Benign

1.0

.;T;T;T;.;.;T;T;T;T

Polyphen

0.0

.;B;B;B;.;.;B;B;B;.

Vest4

0.011, 0.023, 0.033, 0.041, 0.043

MVP

0.31

MPC

0.075

ClinPred

0.0047

GERP RS

-3.0

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.014

gMVP

0.032

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