rs144327167

Positions:

Variant summary

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

The NM_001371623.1(TCOF1):c.1028G>A(p.Ser343Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,571,546 control chromosomes in the GnomAD database, including 11 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 11 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.73

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=0.006667733).

BP6

Variant 5-150374331-G-A is Benign according to our data. Variant chr5-150374331-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 209020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150374331-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00186 (283/152070) while in subpopulation NFE AF= 0.00229 (156/67980). AF 95% confidence interval is 0.002. There are 0 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 283 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1 link	c.1028G>A	p.Ser343Asn	missense_variant	8/27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2 link	c.1028G>A	p.Ser343Asn	missense_variant	8/27		NM_001371623.1	ENSP00000493815.1		Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.00186

AC:

283

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00773

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00229

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00236

AC:

426

AN:

180492

Hom.:

AF XY:

0.00238

AC XY:

229

AN XY:

96090

show subpopulations

Gnomad AFR exome

AF:

0.000470

Gnomad AMR exome

AF:

0.00138

Gnomad ASJ exome

AF:

0.000113

Gnomad EAS exome

AF:

0.0000764

Gnomad SAS exome

AF:

0.00169

Gnomad FIN exome

AF:

0.00822

Gnomad NFE exome

AF:

0.00256

Gnomad OTH exome

AF:

0.00202

GnomAD4 exome

AF:

0.00217

AC:

3078

AN:

1419476

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

1562

AN XY:

702388

show subpopulations

Gnomad4 AFR exome

AF:

0.000186

Gnomad4 AMR exome

AF:

0.00128

Gnomad4 ASJ exome

AF:

0.000118

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00153

Gnomad4 FIN exome

AF:

0.00703

Gnomad4 NFE exome

AF:

0.00221

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00186

AC:

283

AN:

152070

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

162

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000196

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00773

Gnomad4 NFE

AF:

0.00229

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00225

Hom.:

Bravo

AF:

0.00136

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00183

AC:

218

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2019	This variant is associated with the following publications: (PMID: 28419064, 30245029, 28065470, 15340364) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	TCOF1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2019	- -

Treacher Collins syndrome 1

Benign:2

Likely benign, no assertion criteria provided	not provided	Genetics Laboratories, Oxford Radcliffe Hospitals NHS Trust	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

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

Eigen

Benign

-0.062

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.70

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

MetaRNN

Benign

0.0067

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

MetaSVM

Benign

-0.68

MutationAssessor

Pathogenic

3.1

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

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.3

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

REVEL

Benign

0.19

Sift

Uncertain

0.011

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

Sift4G

Uncertain

0.051

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

Polyphen

0.99, 0.21, 0.98, 0.54

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

Vest4

0.37, 0.49, 0.49, 0.47, 0.46

MVP

0.63

MPC

0.43

ClinPred

0.045

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.091

gMVP

0.12

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