rs75583421

Positions:

chr5-150375799-G-A

Variant summary

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

The NM_001371623.1(TCOF1):c.1783G>A(p.Val595Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00956 in 1,614,248 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 10 hom., cov: 34)

Exomes 𝑓: 0.0097 ( 92 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.390

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=0.005758971).

BP6

Variant 5-150375799-G-A is Benign according to our data. Variant chr5-150375799-G-A is described in ClinVar as [Benign]. Clinvar id is 352213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150375799-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00784 (1194/152362) while in subpopulation NFE AF= 0.0111 (756/68028). AF 95% confidence interval is 0.0105. There are 10 homozygotes in gnomad4. There are 603 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1194 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1 linkuse as main transcript	c.1783G>A	p.Val595Ile	missense_variant	12/27	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.1783G>A	p.Val595Ile	missense_variant	12/27		NM_001371623.1	ENSP00000493815	P3	Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.00784

AC:

1194

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00207

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00726

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00746

AC:

1875

AN:

251374

Hom.:

AF XY:

0.00741

AC XY:

1007

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00376

Gnomad ASJ exome

AF:

0.0104

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00124

Gnomad FIN exome

AF:

0.0144

Gnomad NFE exome

AF:

0.0107

Gnomad OTH exome

AF:

0.00750

GnomAD4 exome

AF:

0.00973

AC:

14231

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00960

AC XY:

6983

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.00318

Gnomad4 ASJ exome

AF:

0.00937

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00124

Gnomad4 FIN exome

AF:

0.0135

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00808

GnomAD4 genome

AF:

0.00784

AC:

1194

AN:

152362

Hom.:

Cov.:

AF XY:

0.00809

AC XY:

603

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.00725

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0166

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0100

Hom.:

Bravo

AF:

0.00650

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0117

AC:

101

ExAC

AF:

0.00765

AC:

929

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00981

EpiControl

AF:

0.00942

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TCOF1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2020	This variant is associated with the following publications: (PMID: 28065470) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 13, 2017

- -

Treacher Collins syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

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

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.87

D;T;D;D;.;D;T;T;D;T;.;T

MetaRNN

Benign

0.0058

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

MetaSVM

Benign

-0.88

MutationAssessor

Benign

2.0

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.77

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

REVEL

Benign

0.14

Sift

Uncertain

0.016

.;D;D;D;.;.;.;D;T;D;D;D

Sift4G

Benign

0.16

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

Polyphen

0.95, 0.22

.;P;B;B;.;.;.;B;B;B;P;.

Vest4

0.11, 0.080, 0.074, 0.12, 0.081, 0.14

MVP

0.43

MPC

0.38

ClinPred

0.020

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.062

gMVP

0.047

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