rs15251

chr5-150396669-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001371623.1(TCOF1):c.4172C>T(p.Ala1391Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,610,116 control chromosomes in the GnomAD database, including 58,602 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1391T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.22 (4239 hom., cov: 31)
  • Exomes 𝑓: 0.27 (54363 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.56

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=0.0038337708).
• BP6: Variant 5-150396669-C-T is Benign according to our data. Variant chr5-150396669-C-T is described in ClinVar as [Benign]. Clinvar id is 130574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150396669-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.4172C>T	p.Ala1391Val	missense_variant	24/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.4172C>T	p.Ala1391Val	missense_variant	24/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33216 AN: 151734 Hom.: 4232 Cov.: 31

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.364

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.237

GnomAD3 exomes AF: 0.259 AC: 63514 AN: 245036 Hom.: 8721 AF XY: 0.270 AC XY: 35729 AN XY: 132552

Gnomad AFR exome AF: 0.0752

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.184

Gnomad SAS exome AF: 0.363

Gnomad FIN exome AF: 0.244

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.268 AC: 391363 AN: 1458264 Hom.: 54363 Cov.: 38 AF XY: 0.273 AC XY: 197577 AN XY: 724978

Gnomad4 AFR exome AF: 0.0743

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.371

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.219 AC: 33228 AN: 151852 Hom.: 4239 Cov.: 31 AF XY: 0.220 AC XY: 16340 AN XY: 74166

Gnomad4 AFR AF: 0.0801

Gnomad4 AMR AF: 0.246

Gnomad4 ASJ AF: 0.380

Gnomad4 EAS AF: 0.193

Gnomad4 SAS AF: 0.364

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.236

Alfa AF: 0.268 Hom.: 11820

Bravo AF: 0.208

TwinsUK AF: 0.264 AC: 979

ALSPAC AF: 0.275 AC: 1059

ESP6500AA AF: 0.0876 AC: 386

ESP6500EA AF: 0.273 AC: 2349

ExAC AF: 0.256 AC: 31068

Asia WGS AF: 0.260 AC: 902 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Treacher Collins syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;D;D;.;T
MetaRNN	Benign	0.0038	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.26	T
Polyphen		0.90, 0.56	.;P;P;P;.;.;P;P;P;.
Vest4		0.029, 0.18, 0.17, 0.17
MPC		0.23
ClinPred		0.027	T
GERP RS		2.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.052
gMVP		0.0035

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: rs15251; hg19: chr5-149776232; COSMIC: COSV60347011; COSMIC: COSV60347011;