rs113299143

Positions:

• chr5-150374956-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001371623.1(TCOF1):​c.1281G>A​(p.Ala427=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,612,508 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0036 (23 hom.)
• Consequence: TCOF1 NM_001371623.1 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.45

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-150374956-G-A is Benign according to our data. Variant chr5-150374956-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 209027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150374956-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00283 (427/150692) while in subpopulation NFE AF= 0.00426 (288/67680). AF 95% confidence interval is 0.00385. There are 2 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 427 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.1281G>A	p.Ala427=	splice_region_variant, synonymous_variant	10/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.1281G>A	p.Ala427=	splice_region_variant, synonymous_variant	10/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 427 AN: 150582 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00331

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00183

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.00678

GnomAD3 exomes AF: 0.00279 AC: 695 AN: 248804 Hom.: 4 AF XY: 0.00277 AC XY: 375 AN XY: 135172

Gnomad AFR exome AF: 0.000965

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00412

GnomAD4 exome AF: 0.00358 AC: 5226 AN: 1461816 Hom.: 23 Cov.: 34 AF XY: 0.00341 AC XY: 2482 AN XY: 727206

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.00425

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.00283 AC: 427 AN: 150692 Hom.: 2 Cov.: 34 AF XY: 0.00251 AC XY: 185 AN XY: 73578

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00331

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00183

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.00670

Alfa AF: 0.00356 Hom.: 0

Bravo AF: 0.00300

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

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	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TCOF1: BP4, BP7, BS1, BS2 -
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	GeneDx	Mar 04, 2020	- -

Treacher Collins syndrome 1 Benign:3

Likely benign, no assertion criteria provided	not provided	Genetics Laboratories, Oxford Radcliffe Hospitals NHS Trust	-	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 25, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 10, 2015	- -

TCOF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2021

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.68
DANN	Benign	0.62

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: rs113299143; hg19: chr5-149754519; COSMIC: COSV60350721; COSMIC: COSV60350721;