NM_001371623.1:c.1993G>C

Variant names:

Variant summary

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

The NM_001371623.1(TCOF1):c.1993G>C(p.Ala665Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,614,178 control chromosomes in the GnomAD database, including 5,149 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A665A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.057 ( 336 hom., cov: 34)

Exomes 𝑓: 0.078 ( 4813 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.260

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=0.0017660558).

BP6

Variant 5-150376181-G-C is Benign according to our data. Variant chr5-150376181-G-C is described in ClinVar as [Benign]. Clinvar id is 130566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150376181-G-C is described in Lovd as [Benign]. Variant chr5-150376181-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCOF1	NM_001371623.1 link	c.1993G>C	p.Ala665Pro	missense_variant	Exon 13 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.1993G>C	p.Ala665Pro	missense_variant	Exon 13 of 27		NM_001371623.1	ENSP00000493815.1		Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.0573

AC:

8715

AN:

152200

Hom.:

333

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0143

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.112

Gnomad SAS

AF:

0.0844

Gnomad FIN

AF:

0.0704

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0818

Gnomad OTH

AF:

0.0473

GnomAD3 exomes

AF:

0.0694

AC:

17414

AN:

250932

Hom.:

784

AF XY:

0.0714

AC XY:

9693

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.0133

Gnomad AMR exome

AF:

0.0343

Gnomad ASJ exome

AF:

0.0256

Gnomad EAS exome

AF:

0.127

Gnomad SAS exome

AF:

0.0929

Gnomad FIN exome

AF:

0.0720

Gnomad NFE exome

AF:

0.0763

Gnomad OTH exome

AF:

0.0605

GnomAD4 exome

AF:

0.0779

AC:

113812

AN:

1461860

Hom.:

4813

Cov.:

AF XY:

0.0783

AC XY:

56909

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0120

Gnomad4 AMR exome

AF:

0.0351

Gnomad4 ASJ exome

AF:

0.0248

Gnomad4 EAS exome

AF:

0.0813

Gnomad4 SAS exome

AF:

0.0928

Gnomad4 FIN exome

AF:

0.0713

Gnomad4 NFE exome

AF:

0.0824

Gnomad4 OTH exome

AF:

0.0717

GnomAD4 genome

AF:

0.0573

AC:

8724

AN:

152318

Hom.:

336

Cov.:

AF XY:

0.0575

AC XY:

4281

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0142

Gnomad4 AMR

AF:

0.0408

Gnomad4 ASJ

AF:

0.0225

Gnomad4 EAS

AF:

0.112

Gnomad4 SAS

AF:

0.0842

Gnomad4 FIN

AF:

0.0704

Gnomad4 NFE

AF:

0.0818

Gnomad4 OTH

AF:

0.0510

Alfa

AF:

0.0666

Hom.:

284

Bravo

AF:

0.0516

TwinsUK

AF:

0.0817

AC:

303

ALSPAC

AF:

0.0810

AC:

312

ESP6500AA

AF:

0.0138

AC:

ESP6500EA

AF:

0.0805

AC:

692

ExAC

AF:

0.0691

AC:

8393

Asia WGS

AF:

0.0910

AC:

316

AN:

3478

EpiCase

AF:

0.0728

EpiControl

AF:

0.0703

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Treacher Collins syndrome 1

Benign:1

Feb 03, 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

0.10

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

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

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.71

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

MetaRNN

Benign

0.0018

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

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.6

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

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.3

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

REVEL

Benign

0.18

Sift

Benign

0.053

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

Sift4G

Benign

0.12

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

Polyphen

1.0, 0.99, 0.99

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

Vest4

0.11, 0.20, 0.22, 0.35, 0.22, 0.24

MPC

0.48

ClinPred

0.019

GERP RS

1.9

Varity_R

0.20

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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