rs574569798

chr5-150396821-GAGA-Gchr5-150396821-GAGA-GAGAAGA

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_001371623.1(TCOF1):c.4332_4334del(p.Lys1445del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00343 in 1,605,566 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0035 (12 hom.)
• Consequence: TCOF1 NM_001371623.1 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.69

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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001371623.1. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 5-150396821-GAGA-G is Benign according to our data. Variant chr5-150396821-GAGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 352236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150396821-GAGA-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00322 (490/152156) while in subpopulation NFE AF= 0.0044 (299/68000). AF 95% confidence interval is 0.00399. There are 1 homozygotes in gnomad4. There are 270 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 490 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.4332_4334del	p.Lys1445del	inframe_deletion	24/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.4332_4334del	p.Lys1445del	inframe_deletion	24/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.00322 AC: 490 AN: 152038 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00440

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00313 AC: 720 AN: 229938 Hom.: 4 AF XY: 0.00298 AC XY: 374 AN XY: 125354

Gnomad AFR exome AF: 0.000292

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.0000577

Gnomad SAS exome AF: 0.000313

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.00243

GnomAD4 exome AF: 0.00346 AC: 5023 AN: 1453410 Hom.: 12 AF XY: 0.00336 AC XY: 2429 AN XY: 722212

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.00182

Gnomad4 ASJ exome AF: 0.00135

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000235

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.00372

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00322 AC: 490 AN: 152156 Hom.: 1 Cov.: 30 AF XY: 0.00363 AC XY: 270 AN XY: 74382

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.00440

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00117 Hom.: 1

Bravo AF: 0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TCOF1: PM4:Supporting, BS1 -
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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2019	This variant is associated with the following publications: (PMID: 12444270) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Treacher Collins syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs574569798; hg19: chr5-149776384;