rs137960641

chr5-150393480-G-Achr5-150393480-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001371623.1(TCOF1):c.3712G>A(p.Ala1238Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,614,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (3 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0190

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045256913).
• BP6: Variant 5-150393480-G-A is Benign according to our data. Variant chr5-150393480-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 352232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150393480-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00197 (300/152226) while in subpopulation AFR AF= 0.00578 (240/41530). AF 95% confidence interval is 0.00518. There are 0 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.3712G>A	p.Ala1238Thr	missense_variant	23/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.3712G>A	p.Ala1238Thr	missense_variant	23/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00136 AC: 342 AN: 251428 Hom.: 1 AF XY: 0.00116 AC XY: 157 AN XY: 135896

Gnomad AFR exome AF: 0.00584

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.000557 AC: 815 AN: 1461892 Hom.: 3 Cov.: 31 AF XY: 0.000540 AC XY: 393 AN XY: 727246

Gnomad4 AFR exome AF: 0.00633

Gnomad4 AMR exome AF: 0.00358

Gnomad4 ASJ exome AF: 0.00566

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00172 AC XY: 128 AN XY: 74416

Gnomad4 AFR AF: 0.00578

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000902 Hom.: 1

Bravo AF: 0.00239

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00136 AC: 165

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TCOF1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 18, 2017	- -

Treacher Collins syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

- -

TCOF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 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	0.066
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	1.0
Dann	Benign	0.14
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.62	T;T;T;T;.;T;T;T;.;T
MetaRNN	Benign	0.0045	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
Polyphen		0.0	.;B;B;B;.;.;B;B;B;.
Vest4		0.011, 0.023, 0.033, 0.041, 0.043
MVP		0.31
MPC		0.075
ClinPred		0.0047	T
GERP RS		-3.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.014
gMVP		0.032

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

Other links and lift over

dbSNP: rs137960641; hg19: chr5-149773043; COSMIC: COSV60354443; COSMIC: COSV60354443;