5-150398379-AAAGAAG-AAAG

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001371623.1(TCOF1):c.4380_4382del(p.Lys1461del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,646 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: TCOF1 NM_001371623.1 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 3.32

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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001371623.1
• BP6: Variant 5-150398379-AAAG-A is Benign according to our data. Variant chr5-150398379-AAAG-A is described in ClinVar as [Benign]. Clinvar id is 209016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150398379-AAAG-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00121 (185/152328) while in subpopulation AMR AF= 0.00196 (30/15302). AF 95% confidence interval is 0.00167. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 185 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.4380_4382del	p.Lys1461del	inframe_deletion	25/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.4380_4382del	p.Lys1461del	inframe_deletion	25/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00117 AC: 290 AN: 248098 Hom.: 1 AF XY: 0.00128 AC XY: 172 AN XY: 134446

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.00188 AC: 2754 AN: 1461318 Hom.: 6 AF XY: 0.00183 AC XY: 1333 AN XY: 727000

Gnomad4 AFR exome AF: 0.000390

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00228

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.00121 AC: 185 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74492

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.00129

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Treacher Collins syndrome 1 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Uncertain significance, no assertion criteria provided	not provided	Genetics Laboratories, Oxford Radcliffe Hospitals NHS Trust	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2019

This variant is associated with the following publications: (PMID: 20003452) -

Computational scores

Source: dbNSFP v4.3

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: rs151344581; hg19: chr5-149777942;