rs7713638

Positions:

chr5-150379533-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001371623.1(TCOF1):c.2660T>C(p.Val887Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,614,070 control chromosomes in the GnomAD database, including 21,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V887L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 2669 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18336 hom. )

Consequence

TCOF1
NM_001371623.1 missense, splice_region

Scores

Splicing: ADA: 0.0001368

Clinical Significance

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

Conservation

PhyloP100: -3.97

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041772127).

BP6

Variant 5-150379533-T-C is Benign according to our data. Variant chr5-150379533-T-C is described in ClinVar as [Benign]. Clinvar id is 130569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150379533-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1 linkuse as main transcript	c.2660T>C	p.Val887Ala	missense_variant, splice_region_variant	17/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2 linkuse as main transcript	c.2660T>C	p.Val887Ala	missense_variant, splice_region_variant	17/27		NM_001371623.1	P3	Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

27036

AN:

152088

Hom.:

2663

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.120

Gnomad ASJ

AF:

0.0562

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.158

GnomAD3 exomes

AF:

0.143

AC:

35997

AN:

251068

Hom.:

2947

AF XY:

0.142

AC XY:

19328

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.0846

Gnomad ASJ exome

AF:

0.0619

Gnomad EAS exome

AF:

0.141

Gnomad SAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.139

Gnomad NFE exome

AF:

0.153

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.155

AC:

226007

AN:

1461864

Hom.:

18336

Cov.:

AF XY:

0.154

AC XY:

111784

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.272

Gnomad4 AMR exome

AF:

0.0875

Gnomad4 ASJ exome

AF:

0.0600

Gnomad4 EAS exome

AF:

0.0899

Gnomad4 SAS exome

AF:

0.139

Gnomad4 FIN exome

AF:

0.138

Gnomad4 NFE exome

AF:

0.161

Gnomad4 OTH exome

AF:

0.154

GnomAD4 genome

AF:

0.178

AC:

27081

AN:

152206

Hom.:

2669

Cov.:

AF XY:

0.175

AC XY:

13019

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.267

Gnomad4 AMR

AF:

0.120

Gnomad4 ASJ

AF:

0.0562

Gnomad4 EAS

AF:

0.127

Gnomad4 SAS

AF:

0.127

Gnomad4 FIN

AF:

0.137

Gnomad4 NFE

AF:

0.159

Gnomad4 OTH

AF:

0.160

Alfa

AF:

0.154

Hom.:

3418

Bravo

AF:

0.179

TwinsUK

AF:

0.159

AC:

588

ALSPAC

AF:

0.159

AC:

614

ESP6500AA

AF:

0.255

AC:

1125

ESP6500EA

AF:

0.158

AC:

1362

ExAC

AF:

0.146

AC:

17771

Asia WGS

AF:

0.156

AC:

540

AN:

3478

EpiCase

AF:

0.147

EpiControl

AF:

0.147

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Treacher Collins syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.0060

DANN

Benign

0.39

DEOGEN2

Benign

0.043

.;T;.;.;.;.;.;.;.;.;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.20

T;T;T;T;.;T;T;T;T;T;.;T

MetaRNN

Benign

0.0042

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.26

.;N;.;.;N;.;N;N;N;N;N;.

MutationTaster

Benign

1.0

P;P;P;P;P;P;P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

0.17

.;N;N;N;.;.;.;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.62

.;T;T;T;.;.;.;T;T;T;T;T

Sift4G

Benign

0.89

.;T;T;T;.;.;.;T;T;T;T;T

Polyphen

0.0

.;B;B;B;.;.;.;B;B;B;B;.

Vest4

0.030, 0.014, 0.016, 0.052, 0.013, 0.075

MPC

0.093

ClinPred

0.0051

GERP RS

-7.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.016

gMVP

0.061

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.040

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over