rs528897827

Positions:

• chr5-150372182-TAGTGAGGAGGGATCTGAA-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_001371623.1(TCOF1):​c.827_844del​(p.Gly276_Glu281del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00362 in 1,612,938 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (22 hom.)
• Consequence: TCOF1 NM_001371623.1 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.76

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 -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001371623.1.
• BP6: Variant 5-150372182-TAGTGAGGAGGGATCTGAA-T is Benign according to our data. Variant chr5-150372182-TAGTGAGGAGGGATCTGAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 431981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150372182-TAGTGAGGAGGGATCTGAA-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00257 (388/151240) while in subpopulation AMR AF= 0.00486 (74/15214). AF 95% confidence interval is 0.00397. There are 1 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 388 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1	c.827_844del	p.Gly276_Glu281del	inframe_deletion	7/27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2	c.827_844del	p.Gly276_Glu281del	inframe_deletion	7/27		NM_001371623.1	ENSP00000493815	P3

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 388 AN: 151122 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000755

Gnomad AMI AF: 0.00222

Gnomad AMR AF: 0.00487

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000840

Gnomad FIN AF: 0.00315

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00242

GnomAD3 exomes AF: 0.00196 AC: 488 AN: 248872 Hom.: 4 AF XY: 0.00203 AC XY: 274 AN XY: 135082

Gnomad AFR exome AF: 0.000260

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.00306

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00373 AC: 5458 AN: 1461698 Hom.: 22 AF XY: 0.00358 AC XY: 2605 AN XY: 727146

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00446

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00257 AC: 388 AN: 151240 Hom.: 1 Cov.: 33 AF XY: 0.00259 AC XY: 191 AN XY: 73854

Gnomad4 AFR AF: 0.000753

Gnomad4 AMR AF: 0.00486

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000841

Gnomad4 FIN AF: 0.00315

Gnomad4 NFE AF: 0.00353

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00271

EpiCase AF: 0.00316

EpiControl AF: 0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2019	This variant is associated with the following publications: (PMID: 22317976) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	TCOF1: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 06, 2017

- -

Treacher Collins syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

TCOF1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2020

This variant is classified as likely 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs528897827; hg19: chr5-149751745;