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.4007A>G(p.Lys1336Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,612,838 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 8 hom., cov: 31)

Exomes 𝑓: 0.010 ( 86 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.625

Publications

6 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=0.008495361).

BP6

Variant 5-150396504-A-G is Benign according to our data. Variant chr5-150396504-A-G is described in ClinVar as Benign. ClinVar VariationId is 257553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00853 (1299/152270) while in subpopulation NFE AF = 0.011 (751/68018). AF 95% confidence interval is 0.0104. There are 8 homozygotes in GnomAd4. There are 675 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1299 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.4007A>G	p.Lys1336Arg	missense	Exon 24 of 27	NP_001358552.1
TCOF1	NM_001135243.2		c.4004A>G	p.Lys1335Arg	missense	Exon 24 of 27	NP_001128715.1
TCOF1	NM_001135244.2		c.3893A>G	p.Lys1298Arg	missense	Exon 23 of 26	NP_001128716.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TCOF1	ENST00000643257.2	MANE Select	c.4007A>G	p.Lys1336Arg	missense	Exon 24 of 27	ENSP00000493815.1
TCOF1	ENST00000504761.6	TSL:1	c.4004A>G	p.Lys1335Arg	missense	Exon 24 of 26	ENSP00000421655.2
TCOF1	ENST00000323668.11	TSL:1	c.3773A>G	p.Lys1258Arg	missense	Exon 23 of 26	ENSP00000325223.6

Frequencies

GnomAD3 genomes

AF:

0.00854

AC:

1300

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.00740

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.0208

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.00814

GnomAD2 exomes

AF:

0.00853

AC:

2101

AN:

246186

AF XY:

0.00884

show subpopulations

Gnomad AFR exome

AF:

0.00164

Gnomad AMR exome

AF:

0.00486

Gnomad ASJ exome

AF:

0.00772

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0192

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0102

AC:

14866

AN:

1460568

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

7339

AN XY:

726520

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33442

American (AMR)

AF:

0.00569

AC:

253

AN:

44466

Ashkenazi Jewish (ASJ)

AF:

0.00693

AC:

181

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39656

South Asian (SAS)

AF:

0.00594

AC:

512

AN:

86136

European-Finnish (FIN)

AF:

0.0182

AC:

970

AN:

53170

Middle Eastern (MID)

AF:

0.0129

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0111

AC:

12284

AN:

1111488

Other (OTH)

AF:

0.00890

AC:

537

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1062

2123

3185

4246

5308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.00853

AC:

1299

AN:

152270

Hom.:

Cov.:

AF XY:

0.00907

AC XY:

675

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

41570

American (AMR)

AF:

0.00739

AC:

113

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5148

South Asian (SAS)

AF:

0.00518

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0208

AC:

221

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0110

AC:

751

AN:

68018

Other (OTH)

AF:

0.00806

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

126

190

253

316

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:

0.00953

Hom.:

Bravo

AF:

0.00745

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0100

AC:

ExAC

AF:

0.00850

AC:

1031

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

0.18

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0085

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.2

PhyloP100

0.63

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.32

Sift

Benign

0.13

Sift4G

Benign

0.12

Polyphen

0.13

Vest4

0.073

MVP

0.65

MPC

0.11

ClinPred

0.033

GERP RS

5.0

Varity_R

0.098

gMVP

0.017

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

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rs55980697

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