rs112332762

chr5-150364243-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001371623.1(TCOF1):c.295G>A(p.Ala99Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,614,044 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (13 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.239

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056057572).
• BP6: Variant 5-150364243-G-A is Benign according to our data. Variant chr5-150364243-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257551.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chr5-150364243-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00248 (378/152296) while in subpopulation AMR AF= 0.00347 (53/15292). AF 95% confidence interval is 0.00272. There are 1 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 377 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.295G>A	p.Ala99Thr	missense_variant	3/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.295G>A	p.Ala99Thr	missense_variant	3/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00265 AC: 665 AN: 251328 Hom.: 1 AF XY: 0.00258 AC XY: 351 AN XY: 135876

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00288 AC: 4210 AN: 1461748 Hom.: 13 Cov.: 31 AF XY: 0.00287 AC XY: 2085 AN XY: 727174

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00475

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.00401

Gnomad4 NFE exome AF: 0.00301

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74468

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00303

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00302 Hom.: 4

Bravo AF: 0.00235

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00182 AC: 7

ExAC AF: 0.00292 AC: 355

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 04, 2022	BS1 -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TCOF1: BP4, BS1, BS2 -
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 02, 2024

- -

TCOF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	0.55
Dann	Benign	0.86
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.63	T;T;T;T;.;T;T;T;T;T;T;.;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0056	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
Polyphen		0.046, 0.0060, 0.077, 0.011	.;B;B;B;.;.;.;.;B;B;B;B;.;.
Vest4		0.059, 0.064, 0.065, 0.090, 0.077, 0.094
MVP		0.59
MPC		0.075
ClinPred		0.0042	T
GERP RS		-6.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.018
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: rs112332762; hg19: chr5-149743806; COSMIC: COSV100078617; COSMIC: COSV100078617;