rs73270846

Positions:

chr5-150376525-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001371623.1(TCOF1):c.2245C>T(p.Pro749Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,611,454 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 21 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 23 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.116

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=0.0032149255).

BP6

Variant 5-150376525-C-T is Benign according to our data. Variant chr5-150376525-C-T is described in ClinVar as [Benign]. Clinvar id is 130568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150376525-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0091 (1386/152304) while in subpopulation AFR AF= 0.0303 (1259/41554). AF 95% confidence interval is 0.0289. There are 21 homozygotes in gnomad4. There are 630 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1386 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1 linkuse as main transcript	c.2245C>T	p.Pro749Ser	missense_variant	14/27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2 linkuse as main transcript	c.2245C>T	p.Pro749Ser	missense_variant	14/27		NM_001371623.1	ENSP00000493815	P3	Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.00909

AC:

1384

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0303

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00569

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00242

AC:

591

AN:

243864

Hom.:

AF XY:

0.00170

AC XY:

224

AN XY:

132044

show subpopulations

Gnomad AFR exome

AF:

0.0310

Gnomad AMR exome

AF:

0.00181

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000310

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00106

AC:

1551

AN:

1459150

Hom.:

Cov.:

AF XY:

0.000938

AC XY:

681

AN XY:

725772

show subpopulations

Gnomad4 AFR exome

AF:

0.0314

Gnomad4 AMR exome

AF:

0.00218

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000225

Gnomad4 OTH exome

AF:

0.00232

GnomAD4 genome

AF:

0.00910

AC:

1386

AN:

152304

Hom.:

Cov.:

AF XY:

0.00846

AC XY:

630

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0303

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00992

Alfa

AF:

0.00168

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0302

AC:

133

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00290

AC:

352

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2017	- -
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:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	TCOF1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2020	This variant is associated with the following publications: (PMID: 28065470) -

Treacher Collins syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

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

Eigen

Benign

0.021

Eigen_PC

Benign

-0.076

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.69

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

MetaRNN

Benign

0.0032

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

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.1

.;M;.;.;M;.;M;M;M;M;M;.

MutationTaster

Benign

0.97

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

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-5.5

.;D;D;D;.;.;.;D;D;D;D;D

REVEL

Benign

0.27

Sift

Benign

0.080

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

Sift4G

Benign

0.54

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

Polyphen

0.49, 0.94

.;P;P;P;.;.;.;P;P;P;P;.

Vest4

0.14, 0.11, 0.11, 0.16, 0.15, 0.14

MVP

0.24

MPC

0.099

ClinPred

0.038

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.082

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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