rs114326915

chr5-150374762-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.1229C>T(p.Ser410Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,612,552 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S410P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (27 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.40

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=0.002631545).
• BP6: Variant 5-150374762-C-T is Benign according to our data. Variant chr5-150374762-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 352203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150374762-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1737/151132) while in subpopulation AFR AF= 0.04 (1646/41102). AF 95% confidence interval is 0.0384. There are 31 homozygotes in gnomad4. There are 804 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1727 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.1229C>T	p.Ser410Leu	missense_variant	9/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.1229C>T	p.Ser410Leu	missense_variant	9/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1727 AN: 151010 Hom.: 31 Cov.: 34

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00337

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00333

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00866

GnomAD3 exomes AF: 0.00304 AC: 756 AN: 248284 Hom.: 10 AF XY: 0.00217 AC XY: 292 AN XY: 134440

Gnomad AFR exome AF: 0.0396

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00221

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000896

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00121 AC: 1771 AN: 1461420 Hom.: 27 Cov.: 33 AF XY: 0.00104 AC XY: 756 AN XY: 727006

Gnomad4 AFR exome AF: 0.0402

Gnomad4 AMR exome AF: 0.00247

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000711

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.0115 AC: 1737 AN: 151132 Hom.: 31 Cov.: 34 AF XY: 0.0109 AC XY: 804 AN XY: 73810

Gnomad4 AFR AF: 0.0400

Gnomad4 AMR AF: 0.00330

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00857

Alfa AF: 0.00478 Hom.: 4

Bravo AF: 0.0129

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0368 AC: 162

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00353 AC: 429

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 28065470) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TCOF1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2018	- -

Treacher Collins syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Uncertain	0.98
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.75	T;T;T;T;.;T;T;T;T;T;T;.;T
MetaRNN	Benign	0.0026	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.43	T
Polyphen		0.020, 0.016	.;B;B;B;.;.;.;.;B;B;B;B;.
Vest4		0.19, 0.22, 0.22, 0.24, 0.22, 0.22
MVP		0.26
MPC		0.073
ClinPred		0.014	T
GERP RS		-0.066
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.038

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: rs114326915; hg19: chr5-149754325;