5-150392717-C-G

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.3530C>G(p.Pro1177Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,613,690 control chromosomes in the GnomAD database, including 36,460 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1177H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.16 ( 2581 hom., cov: 33)

Exomes 𝑓: 0.21 ( 33879 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.751

Publications

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

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=0.0053902566).

BP6

Variant 5-150392717-C-G is Benign according to our data. Variant chr5-150392717-C-G is described in ClinVar as Benign. ClinVar VariationId is 130571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371623.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCOF1	NM_001371623.1	MANE Select	c.3530C>G	p.Pro1177Arg	missense	Exon 22 of 27	NP_001358552.1	Q13428-3
TCOF1	NM_001135243.2		c.3527C>G	p.Pro1176Arg	missense	Exon 22 of 27	NP_001128715.1	Q13428-1
TCOF1	NM_001135244.2		c.3416C>G	p.Pro1139Arg	missense	Exon 21 of 26	NP_001128716.1	Q13428-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCOF1	ENST00000643257.2	MANE Select	c.3530C>G	p.Pro1177Arg	missense	Exon 22 of 27	ENSP00000493815.1	Q13428-3
TCOF1	ENST00000504761.6	TSL:1	c.3527C>G	p.Pro1176Arg	missense	Exon 22 of 26	ENSP00000421655.2	Q13428-1
TCOF1	ENST00000323668.11	TSL:1	c.3296C>G	p.Pro1099Arg	missense	Exon 21 of 26	ENSP00000325223.6	Q13428-2

Frequencies

GnomAD3 genomes

AF:

0.160

AC:

24315

AN:

152094

Hom.:

2580

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0410

Gnomad AMI

AF:

0.434

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.000966

Gnomad SAS

AF:

0.0836

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.233

Gnomad OTH

AF:

0.161

GnomAD2 exomes

AF:

0.167

AC:

41803

AN:

249902

AF XY:

0.170

show subpopulations

Gnomad AFR exome

AF:

0.0362

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.224

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.235

Gnomad OTH exome

AF:

0.196

GnomAD4 exome

AF:

0.206

AC:

301223

AN:

1461478

Hom.:

33879

Cov.:

AF XY:

0.204

AC XY:

148233

AN XY:

727038

show subpopulations

African (AFR)

AF:

0.0327

AC:

1096

AN:

33476

American (AMR)

AF:

0.106

AC:

4718

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

5861

AN:

26130

East Asian (EAS)

AF:

0.000327

AC:

AN:

39698

South Asian (SAS)

AF:

0.0918

AC:

7914

AN:

86248

European-Finnish (FIN)

AF:

0.240

AC:

12777

AN:

53288

Middle Eastern (MID)

AF:

0.132

AC:

758

AN:

5760

European-Non Finnish (NFE)

AF:

0.231

AC:

256961

AN:

1111794

Other (OTH)

AF:

0.184

AC:

11125

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

13204

26408

39611

52815

66019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8482

16964

25446

33928

42410

<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:

0.160

AC:

24316

AN:

152212

Hom.:

2581

Cov.:

AF XY:

0.156

AC XY:

11621

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0409

AC:

1701

AN:

41558

American (AMR)

AF:

0.143

AC:

2187

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

756

AN:

3472

East Asian (EAS)

AF:

0.000968

AC:

AN:

5166

South Asian (SAS)

AF:

0.0843

AC:

407

AN:

4828

European-Finnish (FIN)

AF:

0.249

AC:

2633

AN:

10588

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.233

AC:

15854

AN:

67984

Other (OTH)

AF:

0.160

AC:

339

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1043

2087

3130

4174

5217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.200

Hom.:

2517

Bravo

AF:

0.149

TwinsUK

AF:

0.243

AC:

901

ALSPAC

AF:

0.226

AC:

872

ESP6500AA

AF:

0.0456

AC:

201

ESP6500EA

AF:

0.235

AC:

2018

ExAC

AF:

0.169

AC:

20570

EpiCase

AF:

0.224

EpiControl

AF:

0.229

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

0.75

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.11

Sift

Benign

0.046

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.16

MPC

0.27

ClinPred

0.037

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.086

gMVP

0.074

Mutation Taster

=95/5

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over