rs45491898

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.4295G>C(p.Gly1432Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,610,616 control chromosomes in the GnomAD database, including 444 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1432R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.018 ( 43 hom., cov: 31)

Exomes 𝑓: 0.022 ( 401 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.836

Publications

22 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=0.0030030906).

BP6

Variant 5-150396792-G-C is Benign according to our data. Variant chr5-150396792-G-C is described in ClinVar as [Benign]. Clinvar id is 130575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0178 (2711/152132) while in subpopulation AMR AF = 0.0294 (449/15278). AF 95% confidence interval is 0.0271. There are 43 homozygotes in GnomAd4. There are 1351 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 2711 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCOF1	NM_001371623.1 link	c.4295G>C	p.Gly1432Ala	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.4295G>C	p.Gly1432Ala	missense_variant	Exon 24 of 27		NM_001371623.1	ENSP00000493815.1		Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2710

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00420

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.0294

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00911

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0248

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0185

AC:

4478

AN:

242024

AF XY:

0.0189

show subpopulations

Gnomad AFR exome

AF:

0.00364

Gnomad AMR exome

AF:

0.0201

Gnomad ASJ exome

AF:

0.0328

Gnomad EAS exome

AF:

0.0000554

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.0258

Gnomad OTH exome

AF:

0.0217

GnomAD4 exome

AF:

0.0217

AC:

31697

AN:

1458484

Hom.:

401

Cov.:

AF XY:

0.0216

AC XY:

15635

AN XY:

725228

show subpopulations

African (AFR)

AF:

0.00409

AC:

137

AN:

33460

American (AMR)

AF:

0.0213

AC:

943

AN:

44252

Ashkenazi Jewish (ASJ)

AF:

0.0334

AC:

872

AN:

26088

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39666

South Asian (SAS)

AF:

0.00830

AC:

712

AN:

85828

European-Finnish (FIN)

AF:

0.0136

AC:

710

AN:

52296

Middle Eastern (MID)

AF:

0.0270

AC:

155

AN:

5738

European-Non Finnish (NFE)

AF:

0.0243

AC:

26958

AN:

1110854

Other (OTH)

AF:

0.0200

AC:

1208

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1942

3884

5827

7769

9711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0178

AC:

2711

AN:

152132

Hom.:

Cov.:

AF XY:

0.0182

AC XY:

1351

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00417

AC:

173

AN:

41514

American (AMR)

AF:

0.0294

AC:

449

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0323

AC:

112

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00911

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0113

AC:

120

AN:

10606

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0248

AC:

1687

AN:

67978

Other (OTH)

AF:

0.0237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

130

261

391

522

652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0242

Hom.:

Bravo

AF:

0.0185

TwinsUK

AF:

0.0229

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0212

AC:

182

ExAC

AF:

0.0175

AC:

2120

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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. -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >3% in Exome Aggregation Consortium (European non-Finnish population). -

not provided

Benign:2

Nov 14, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

Jan 30, 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

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

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

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.88

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

MetaRNN

Benign

0.0030

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

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.8

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

PhyloP100

0.84

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.8

.;D;D;D;.;.;D;D;D;D;N

REVEL

Benign

0.19

Sift

Benign

0.042

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

Sift4G

Uncertain

0.047

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

Polyphen

0.41, 0.93

.;B;P;P;.;.;P;P;B;.;.

Vest4

0.098, 0.19, 0.19, 0.29, 0.28

MPC

0.41

ClinPred

0.018

GERP RS

0.69

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.14

gMVP

0.0024

Mutation Taster

=99/1

polymorphism (auto)

(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

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rs45491898

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