NM_001371623.1:c.1229C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S410P) has been classified as Uncertain significance.

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

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Treacher Collins syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Treacher-Collins syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

TCOF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 352203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 1737 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCOF1	NM_001371623.1 link	c.1229C>T	p.Ser410Leu	missense_variant	Exon 9 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.1229C>T	p.Ser410Leu	missense_variant	Exon 9 of 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

GnomAD2 exomes

AF:

0.00304

AC:

756

AN:

248284

AF XY:

0.00217

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 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

African (AFR)

AF:

0.0402

AC:

1347

AN:

33470

American (AMR)

AF:

0.00247

AC:

110

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000711

AC:

AN:

1111804

Other (OTH)

AF:

0.00280

AC:

169

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

116

232

349

465

581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0115

AC:

1737

AN:

151132

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

804

AN XY:

73810

show subpopulations

African (AFR)

AF:

0.0400

AC:

1646

AN:

41102

American (AMR)

AF:

0.00330

AC:

AN:

15166

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.000209

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10428

Middle Eastern (MID)

AF:

0.00357

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

67806

Other (OTH)

AF:

0.00857

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

152

228

304

380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00469

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

May 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 17, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TCOF1: BP4, BS1, BS2 -

not specified

Benign:2

Sep 11, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 09, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Treacher Collins syndrome 1

Benign:1

Dec 30, 2024

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

0.078

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

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;.

PhyloP100

1.4

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

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over