rs112332762

Positions:

chr5-150364243-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001371623.1(TCOF1):c.295G>A(p.Ala99Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,614,044 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 13 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.239

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056057572).

BP6

Variant 5-150364243-G-A is Benign according to our data. Variant chr5-150364243-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257551.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr5-150364243-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00248 (378/152296) while in subpopulation AMR AF= 0.00347 (53/15292). AF 95% confidence interval is 0.00272. There are 1 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 378 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1 linkuse as main transcript	c.295G>A	p.Ala99Thr	missense_variant	3/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2 linkuse as main transcript	c.295G>A	p.Ala99Thr	missense_variant	3/27		NM_001371623.1	P3	Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00354

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00303

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00265

AC:

665

AN:

251328

Hom.:

AF XY:

0.00258

AC XY:

351

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00292

Gnomad ASJ exome

AF:

0.00476

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.00374

Gnomad NFE exome

AF:

0.00327

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00288

AC:

4210

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00287

AC XY:

2085

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00282

Gnomad4 ASJ exome

AF:

0.00475

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000730

Gnomad4 FIN exome

AF:

0.00401

Gnomad4 NFE exome

AF:

0.00301

Gnomad4 OTH exome

AF:

0.00305

GnomAD4 genome

AF:

0.00248

AC:

378

AN:

152296

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

173

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.00347

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00330

Gnomad4 NFE

AF:

0.00303

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00302

Hom.:

Bravo

AF:

0.00235

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00182

AC:

ExAC

AF:

0.00292

AC:

355

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 04, 2022	BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TCOF1: BP4, BS1 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Treacher Collins syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

- -

TCOF1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.55

DANN

Benign

0.86

DEOGEN2

Benign

0.17

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

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.63

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

M_CAP

Benign

0.029

MetaRNN

Benign

0.0056

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

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

.;L;L;L;L;.;.;L;L;L;L;L;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.6

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

REVEL

Benign

0.16

Sift

Benign

0.35

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

Sift4G

Benign

0.59

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

Polyphen

0.046, 0.0060, 0.077, 0.011

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

Vest4

0.059, 0.064, 0.065, 0.090, 0.077, 0.094

MVP

0.59

MPC

0.075

ClinPred

0.0042

GERP RS

-6.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.018

gMVP

0.15

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

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