rs150515843

Positions:

• chr5-150379635-C-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.2762C>T​(p.Pro921Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000939 in 1,614,178 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (7 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 1.36

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=0.0034576058).
• BP6: Variant 5-150379635-C-T is Benign according to our data. Variant chr5-150379635-C-T is described in ClinVar as [Benign]. Clinvar id is 209031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150379635-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00496 (756/152316) while in subpopulation AFR AF= 0.0172 (713/41564). AF 95% confidence interval is 0.0161. There are 5 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 756 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.2762C>T	p.Pro921Leu	missense_variant	17/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.2762C>T	p.Pro921Leu	missense_variant	17/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152198 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00119 AC: 300 AN: 251198 Hom.: 4 AF XY: 0.000943 AC XY: 128 AN XY: 135778

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000520 AC: 760 AN: 1461862 Hom.: 7 Cov.: 31 AF XY: 0.000481 AC XY: 350 AN XY: 727232

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00496 AC: 756 AN: 152316 Hom.: 5 Cov.: 32 AF XY: 0.00483 AC XY: 360 AN XY: 74490

Gnomad4 AFR AF: 0.0172

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00243 Hom.: 3

Bravo AF: 0.00568

ESP6500AA AF: 0.0161 AC: 71

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Eurofins Ntd Llc (ga)	Jul 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2020	This variant is associated with the following publications: (PMID: 28065470) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Treacher Collins syndrome 1 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	not provided	Genetics Laboratories, Oxford Radcliffe Hospitals NHS Trust	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Benign	0.97
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.91	D;D;D;D;.;D;D;D;T;D;.;D
MetaRNN	Benign	0.0035	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
Polyphen		0.40, 0.62, 0.91	.;B;P;P;.;.;.;P;P;P;B;.
Vest4		0.061, 0.12, 0.089, 0.091, 0.086, 0.093
MVP		0.33
MPC		0.44
ClinPred		0.10	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.15

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: rs150515843; hg19: chr5-149759198; COSMIC: COSV105181578; COSMIC: COSV105181578;