rs114326915

Positions:

chr5-150374762-C-T

Variant summary

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

The NM_001371623.1(TCOF1):c.1229C>T(p.Ser410Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,612,552 control chromosomes in the GnomAD database, including 58 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 31 hom., cov: 34)

Exomes 𝑓: 0.0012 ( 27 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.40

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=0.002631545).

BP6

Variant 5-150374762-C-T is Benign according to our data. Variant chr5-150374762-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 352203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150374762-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1737/151132) while in subpopulation AFR AF= 0.04 (1646/41102). AF 95% confidence interval is 0.0384. There are 31 homozygotes in gnomad4. There are 804 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1737 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1 link	c.1229C>T	p.Ser410Leu	missense_variant	9/27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2 link	c.1229C>T	p.Ser410Leu	missense_variant	9/27		NM_001371623.1	ENSP00000493815.1		Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1727

AN:

151010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0399

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00337

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00333

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00866

GnomAD3 exomes

AF:

0.00304

AC:

756

AN:

248284

Hom.:

AF XY:

0.00217

AC XY:

292

AN XY:

134440

show subpopulations

Gnomad AFR exome

AF:

0.0396

Gnomad AMR exome

AF:

0.00230

Gnomad ASJ exome

AF:

0.00221

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000896

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.00121

AC:

1771

AN:

1461420

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

756

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.0402

Gnomad4 AMR exome

AF:

0.00247

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000711

Gnomad4 OTH exome

AF:

0.00280

GnomAD4 genome

AF:

0.0115

AC:

1737

AN:

151132

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

804

AN XY:

73810

show subpopulations

Gnomad4 AFR

AF:

0.0400

Gnomad4 AMR

AF:

0.00330

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00857

Alfa

AF:

0.00478

Hom.:

Bravo

AF:

0.0129

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0368

AC:

162

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00353

AC:

429

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TCOF1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 28065470) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2018	- -

Treacher Collins syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

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

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.75

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

MetaRNN

Benign

0.0026

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

.;M;.;.;M;.;.;M;M;M;M;M;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.5

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

REVEL

Benign

0.18

Sift

Benign

0.040

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

Sift4G

Uncertain

0.017

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

Polyphen

0.020, 0.016

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

Vest4

0.19, 0.22, 0.22, 0.24, 0.22, 0.22

MVP

0.26

MPC

0.073

ClinPred

0.014

GERP RS

-0.066

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.051

gMVP

0.038

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