rs55980697

Variant names:

Variant summary

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

The NM_001371623.1(TCOF1):c.4007A>G(p.Lys1336Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,612,838 control chromosomes in the GnomAD database, including 94 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 (★★).

Frequency

Genomes: 𝑓 0.0085 ( 8 hom., cov: 31)

Exomes 𝑓: 0.010 ( 86 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.625

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=0.008495361).

BP6

Variant 5-150396504-A-G is Benign according to our data. Variant chr5-150396504-A-G is described in ClinVar as [Benign]. Clinvar id is 257553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150396504-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00853 (1299/152270) while in subpopulation NFE AF= 0.011 (751/68018). AF 95% confidence interval is 0.0104. There are 8 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1299 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCOF1	NM_001371623.1 link	c.4007A>G	p.Lys1336Arg	missense_variant	Exon 24 of 27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2 link	c.4007A>G	p.Lys1336Arg	missense_variant	Exon 24 of 27		NM_001371623.1	ENSP00000493815.1		Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.00854

AC:

1300

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.00740

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.0208

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.00814

GnomAD3 exomes

AF:

0.00853

AC:

2101

AN:

246186

Hom.:

AF XY:

0.00884

AC XY:

1182

AN XY:

133642

show subpopulations

Gnomad AFR exome

AF:

0.00164

Gnomad AMR exome

AF:

0.00486

Gnomad ASJ exome

AF:

0.00772

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00599

Gnomad FIN exome

AF:

0.0192

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0102

AC:

14866

AN:

1460568

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

7339

AN XY:

726520

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.00569

Gnomad4 ASJ exome

AF:

0.00693

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00594

Gnomad4 FIN exome

AF:

0.0182

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.00890

GnomAD4 genome

AF:

0.00853

AC:

1299

AN:

152270

Hom.:

Cov.:

AF XY:

0.00907

AC XY:

675

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.00739

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.0208

Gnomad4 NFE

AF:

0.0110

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.00973

Hom.:

Bravo

AF:

0.00745

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0100

AC:

ExAC

AF:

0.00850

AC:

1031

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TCOF1: BP4, BS1, BS2 -

May 15, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28065470) -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Treacher Collins syndrome 1

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

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

Eigen

Benign

0.18

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.68

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

MetaRNN

Benign

0.0085

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

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.2

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

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.9

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

REVEL

Uncertain

0.32

Sift

Benign

0.13

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

Sift4G

Benign

0.12

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

Polyphen

0.13, 1.0

.;B;D;D;.;.;D;D;B;.

Vest4

0.073, 0.13, 0.13, 0.13, 0.12

MVP

0.65

MPC

0.11

ClinPred

0.033

GERP RS

5.0

Varity_R

0.098

gMVP

0.017

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