rs7713638

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001371623.1(TCOF1):c.2660T>C(p.Val887Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,614,070 control chromosomes in the GnomAD database, including 21,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V887L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 2669 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18336 hom. )

Consequence

TCOF1
NM_001371623.1 missense, splice_region

Scores

Splicing: ADA: 0.0001368

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.97

Publications

33 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=0.0041772127).

BP6

Variant 5-150379533-T-C is Benign according to our data. Variant chr5-150379533-T-C is described in ClinVar as [Benign]. Clinvar id is 130569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCOF1	NM_001371623.1 link	c.2660T>C	p.Val887Ala	missense_variant, splice_region_variant	Exon 17 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.2660T>C	p.Val887Ala	missense_variant, splice_region_variant	Exon 17 of 27		NM_001371623.1	ENSP00000493815.1		Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

27036

AN:

152088

Hom.:

2663

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.120

Gnomad ASJ

AF:

0.0562

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.158

GnomAD2 exomes

AF:

0.143

AC:

35997

AN:

251068

AF XY:

0.142

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.0846

Gnomad ASJ exome

AF:

0.0619

Gnomad EAS exome

AF:

0.141

Gnomad FIN exome

AF:

0.139

Gnomad NFE exome

AF:

0.153

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.155

AC:

226007

AN:

1461864

Hom.:

18336

Cov.:

AF XY:

0.154

AC XY:

111784

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.272

AC:

9107

AN:

33480

American (AMR)

AF:

0.0875

AC:

3915

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0600

AC:

1567

AN:

26136

East Asian (EAS)

AF:

0.0899

AC:

3570

AN:

39700

South Asian (SAS)

AF:

0.139

AC:

11962

AN:

86258

European-Finnish (FIN)

AF:

0.138

AC:

7343

AN:

53396

Middle Eastern (MID)

AF:

0.109

AC:

629

AN:

5768

European-Non Finnish (NFE)

AF:

0.161

AC:

178642

AN:

1112008

Other (OTH)

AF:

0.154

AC:

9272

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

13401

26803

40204

53606

67007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.178

AC:

27081

AN:

152206

Hom.:

2669

Cov.:

AF XY:

0.175

AC XY:

13019

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.267

AC:

11086

AN:

41524

American (AMR)

AF:

0.120

AC:

1838

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0562

AC:

195

AN:

3472

East Asian (EAS)

AF:

0.127

AC:

659

AN:

5176

South Asian (SAS)

AF:

0.127

AC:

612

AN:

4822

European-Finnish (FIN)

AF:

0.137

AC:

1449

AN:

10598

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.159

AC:

10778

AN:

67992

Other (OTH)

AF:

0.160

AC:

339

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1161

2323

3484

4646

5807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.156

Hom.:

4996

Bravo

AF:

0.179

TwinsUK

AF:

0.159

AC:

588

ALSPAC

AF:

0.159

AC:

614

ESP6500AA

AF:

0.255

AC:

1125

ESP6500EA

AF:

0.158

AC:

1362

ExAC

AF:

0.146

AC:

17771

Asia WGS

AF:

0.156

AC:

540

AN:

3478

EpiCase

AF:

0.147

EpiControl

AF:

0.147

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:1

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

0.068

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.0060

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.043

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

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.20

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

MetaRNN

Benign

0.0042

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.26

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

PhyloP100

-4.0

PrimateAI

Benign

0.30

PROVEAN

Benign

0.17

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

REVEL

Benign

0.12

Sift

Benign

0.62

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

Sift4G

Benign

0.89

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

Polyphen

0.0

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

Vest4

0.030, 0.014, 0.016, 0.052, 0.013, 0.075

MPC

0.093

ClinPred

0.0051

GERP RS

-7.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.016

gMVP

0.061

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.040

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs7713638

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