dbSNP rs112039991: TCOF1:p.Ala374Ser (chr5-150374653-G-T) – ACMG Classification: Benign (-20 pts)

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.1120G>T(p.Ala374Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,613,768 control chromosomes in the GnomAD database, including 8 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A374A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00047 ( 7 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.45

Publications

3 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=0.005467236).

BP6

Variant 5-150374653-G-T is Benign according to our data. Variant chr5-150374653-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 352200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00098 (149/152014) while in subpopulation SAS AF = 0.00561 (27/4812). AF 95% confidence interval is 0.00396. There are 1 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 149 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	UniProt
TCOF1	NM_001371623.1	MANE Select	c.1120G>T	p.Ala374Ser	missense	Exon 9 of 27	NP_001358552.1	Q13428-3
TCOF1	NM_001135243.2		c.1120G>T	p.Ala374Ser	missense	Exon 9 of 27	NP_001128715.1	Q13428-1
TCOF1	NM_001135244.2		c.1120G>T	p.Ala374Ser	missense	Exon 9 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.1120G>T	p.Ala374Ser	missense	Exon 9 of 27	ENSP00000493815.1	Q13428-3
TCOF1	ENST00000504761.6	TSL:1	c.1120G>T	p.Ala374Ser	missense	Exon 9 of 26	ENSP00000421655.2	Q13428-1
TCOF1	ENST00000323668.11	TSL:1	c.889G>T	p.Ala297Ser	missense	Exon 8 of 26	ENSP00000325223.6	Q13428-2

Frequencies

GnomAD3 genomes

AF:

0.000915

AC:

139

AN:

151896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00136

Gnomad SAS

AF:

0.00561

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000901

AC:

225

AN:

249620

AF XY:

0.00102

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000924

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.000473

AC:

691

AN:

1461754

Hom.:

Cov.:

AF XY:

0.000600

AC XY:

436

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00317

AC:

106

AN:

33476

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000302

AC:

AN:

39698

South Asian (SAS)

AF:

0.00499

AC:

430

AN:

86254

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00159

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1112004

Other (OTH)

AF:

0.00161

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000980

AC:

149

AN:

152014

Hom.:

Cov.:

AF XY:

0.000996

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.00270

AC:

112

AN:

41430

American (AMR)

AF:

0.000131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00136

AC:

AN:

5148

South Asian (SAS)

AF:

0.00561

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000351

Hom.:

Bravo

AF:

0.000774

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00117

AC:

142

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.7

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.18

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.6

PhyloP100

1.4

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.84

REVEL

Benign

0.10

Sift

Benign

0.069

Sift4G

Benign

0.49

Polyphen

0.47

Vest4

0.23

MVP

0.44

MPC

0.17

ClinPred

0.0085

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.029

gMVP

0.017

Mutation Taster

=100/0

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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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