rs73270846

chr5-150376525-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.2245C>T(p.Pro749Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,611,454 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (21 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.116

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=0.0032149255).
• BP6: Variant 5-150376525-C-T is Benign according to our data. Variant chr5-150376525-C-T is described in ClinVar as [Benign]. Clinvar id is 130568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150376525-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0091 (1386/152304) while in subpopulation AFR AF= 0.0303 (1259/41554). AF 95% confidence interval is 0.0289. There are 21 homozygotes in gnomad4. There are 630 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1384 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.2245C>T	p.Pro749Ser	missense_variant	14/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.2245C>T	p.Pro749Ser	missense_variant	14/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.00909 AC: 1384 AN: 152186 Hom.: 21 Cov.: 34

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00242 AC: 591 AN: 243864 Hom.: 6 AF XY: 0.00170 AC XY: 224 AN XY: 132044

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.00181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00106 AC: 1551 AN: 1459150 Hom.: 23 Cov.: 34 AF XY: 0.000938 AC XY: 681 AN XY: 725772

Gnomad4 AFR exome AF: 0.0314

Gnomad4 AMR exome AF: 0.00218

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000225

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00910 AC: 1386 AN: 152304 Hom.: 21 Cov.: 34 AF XY: 0.00846 AC XY: 630 AN XY: 74472

Gnomad4 AFR AF: 0.0303

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00168 Hom.: 10

Bravo AF: 0.0108

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0302 AC: 133

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00290 AC: 352

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Eurofins Ntd Llc (ga)	Sep 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2020	This variant is associated with the following publications: (PMID: 28065470) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	TCOF1: BP4, BS1, BS2 -

Treacher Collins syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	10
Dann	Uncertain	1.0
Eigen	Benign	0.021
Eigen_PC	Benign	-0.076
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.69	T;T;T;T;.;T;T;T;T;T;.;T
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	0.97	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
Polyphen		0.49, 0.94	.;P;P;P;.;.;.;P;P;P;P;.
Vest4		0.14, 0.11, 0.11, 0.16, 0.15, 0.14
MVP		0.24
MPC		0.099
ClinPred		0.038	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.082
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs73270846; hg19: chr5-149756088;