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.1133C>T(p.Ala378Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,613,948 control chromosomes in the GnomAD database, including 70 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 (★★).

Frequency

Genomes: 𝑓 0.011 ( 40 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 30 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0560

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=0.0040968657).

BP6

Variant 5-150374666-C-T is Benign according to our data. Variant chr5-150374666-C-T is described in ClinVar as Benign. ClinVar VariationId is 352202.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 = 0.0108 (1641/152130) while in subpopulation AFR AF = 0.0372 (1543/41470). AF 95% confidence interval is 0.0357. There are 40 homozygotes in GnomAd4. There are 737 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 1641 AD gene.

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
TCOF1	NM_001371623.1	MANE Select	c.1133C>T	p.Ala378Val	missense	Exon 9 of 27	NP_001358552.1
TCOF1	NM_001135243.2		c.1133C>T	p.Ala378Val	missense	Exon 9 of 27	NP_001128715.1
TCOF1	NM_001135244.2		c.1133C>T	p.Ala378Val	missense	Exon 9 of 26	NP_001128716.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TCOF1	ENST00000643257.2	MANE Select	c.1133C>T	p.Ala378Val	missense	Exon 9 of 27	ENSP00000493815.1
TCOF1	ENST00000504761.6	TSL:1	c.1133C>T	p.Ala378Val	missense	Exon 9 of 26	ENSP00000421655.2
TCOF1	ENST00000323668.11	TSL:1	c.902C>T	p.Ala301Val	missense	Exon 8 of 26	ENSP00000325223.6

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1643

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0374

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00472

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00283

AC:

706

AN:

249788

AF XY:

0.00192

show subpopulations

Gnomad AFR exome

AF:

0.0385

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000802

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00107

AC:

1566

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000901

AC XY:

655

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0377

AC:

1262

AN:

33478

American (AMR)

AF:

0.00239

AC:

107

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000162

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1112002

Other (OTH)

AF:

0.00265

AC:

160

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

105

210

314

419

524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.0108

AC:

1641

AN:

152130

Hom.:

Cov.:

AF XY:

0.00991

AC XY:

737

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0372

AC:

1543

AN:

41470

American (AMR)

AF:

0.00471

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68008

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

153

229

306

382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00290

Hom.:

Bravo

AF:

0.0123

ESP6500AA

AF:

0.0357

AC:

157

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00352

AC:

427

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

PhyloP100

0.056

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

REVEL

Benign

0.084

Sift

Benign

0.090

Sift4G

Benign

0.23

Polyphen

0.19

Vest4

0.13

MVP

0.42

MPC

0.17

ClinPred

0.0049

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.061

gMVP

0.024

Mutation Taster

=96/4

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.

NM_001371623.1:c.1133C>T

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over