rs15251

Positions:

chr5-150396669-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001371623.1(TCOF1):c.4172C>T(p.Ala1391Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,610,116 control chromosomes in the GnomAD database, including 58,602 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1391T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.22 ( 4239 hom., cov: 31)

Exomes 𝑓: 0.27 ( 54363 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.56

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038337708).

BP6

Variant 5-150396669-C-T is Benign according to our data. Variant chr5-150396669-C-T is described in ClinVar as [Benign]. Clinvar id is 130574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150396669-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1 linkuse as main transcript	c.4172C>T	p.Ala1391Val	missense_variant	24/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2 linkuse as main transcript	c.4172C>T	p.Ala1391Val	missense_variant	24/27		NM_001371623.1	P3	Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33216

AN:

151734

Hom.:

4232

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0803

Gnomad AMI

AF:

0.293

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.380

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.364

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.237

GnomAD3 exomes

AF:

0.259

AC:

63514

AN:

245036

Hom.:

8721

AF XY:

0.270

AC XY:

35729

AN XY:

132552

show subpopulations

Gnomad AFR exome

AF:

0.0752

Gnomad AMR exome

AF:

0.230

Gnomad ASJ exome

AF:

0.365

Gnomad EAS exome

AF:

0.184

Gnomad SAS exome

AF:

0.363

Gnomad FIN exome

AF:

0.244

Gnomad NFE exome

AF:

0.270

Gnomad OTH exome

AF:

0.285

GnomAD4 exome

AF:

0.268

AC:

391363

AN:

1458264

Hom.:

54363

Cov.:

AF XY:

0.273

AC XY:

197577

AN XY:

724978

show subpopulations

Gnomad4 AFR exome

AF:

0.0743

Gnomad4 AMR exome

AF:

0.235

Gnomad4 ASJ exome

AF:

0.371

Gnomad4 EAS exome

AF:

0.185

Gnomad4 SAS exome

AF:

0.361

Gnomad4 FIN exome

AF:

0.250

Gnomad4 NFE exome

AF:

0.269

Gnomad4 OTH exome

AF:

0.272

GnomAD4 genome

AF:

0.219

AC:

33228

AN:

151852

Hom.:

4239

Cov.:

AF XY:

0.220

AC XY:

16340

AN XY:

74166

show subpopulations

Gnomad4 AFR

AF:

0.0801

Gnomad4 AMR

AF:

0.246

Gnomad4 ASJ

AF:

0.380

Gnomad4 EAS

AF:

0.193

Gnomad4 SAS

AF:

0.364

Gnomad4 FIN

AF:

0.241

Gnomad4 NFE

AF:

0.275

Gnomad4 OTH

AF:

0.236

Alfa

AF:

0.268

Hom.:

11820

Bravo

AF:

0.208

TwinsUK

AF:

0.264

AC:

979

ALSPAC

AF:

0.275

AC:

1059

ESP6500AA

AF:

0.0876

AC:

386

ESP6500EA

AF:

0.273

AC:

2349

ExAC

AF:

0.256

AC:

31068

Asia WGS

AF:

0.260

AC:

902

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Treacher Collins syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

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

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.90

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

MetaRNN

Benign

0.0038

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

.;L;.;.;.;.;.;.;L;.

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.5

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

REVEL

Benign

0.15

Sift

Uncertain

0.013

.;.;D;D;.;.;D;D;D;D

Sift4G

Benign

0.062

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

Polyphen

0.90, 0.56

.;P;P;P;.;.;P;P;P;.

Vest4

0.029, 0.18, 0.17, 0.17

MPC

0.23

ClinPred

0.027

GERP RS

2.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.052

gMVP

0.0035

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