rs55980697

Positions:

• chr5-150396504-A-G

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.4007A>G​(p.Lys1336Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,612,838 control chromosomes in the GnomAD database, including 94 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (8 hom., cov: 31)
  • Exomes 𝑓: 0.010 (86 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.625

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=0.008495361).
• BP6: Variant 5-150396504-A-G is Benign according to our data. Variant chr5-150396504-A-G is described in ClinVar as [Benign]. Clinvar id is 257553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150396504-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00853 (1299/152270) while in subpopulation NFE AF= 0.011 (751/68018). AF 95% confidence interval is 0.0104. There are 8 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1299 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.4007A>G	p.Lys1336Arg	missense_variant	24/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.4007A>G	p.Lys1336Arg	missense_variant	24/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.00854 AC: 1300 AN: 152152 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00853 AC: 2101 AN: 246186 Hom.: 20 AF XY: 0.00884 AC XY: 1182 AN XY: 133642

Gnomad AFR exome AF: 0.00164

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.00772

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00599

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0102 AC: 14866 AN: 1460568 Hom.: 86 Cov.: 31 AF XY: 0.0101 AC XY: 7339 AN XY: 726520

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00569

Gnomad4 ASJ exome AF: 0.00693

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00594

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00890

GnomAD4 genome AF: 0.00853 AC: 1299 AN: 152270 Hom.: 8 Cov.: 31 AF XY: 0.00907 AC XY: 675 AN XY: 74448

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0208

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00973 Hom.: 13

Bravo AF: 0.00745

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00850 AC: 1031

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: 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	Athena Diagnostics	May 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	TCOF1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2020	This variant is associated with the following publications: (PMID: 28065470) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2017	- -

Treacher Collins syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	1.0
Eigen	Benign	0.18
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.68	T;T;T;T;.;T;T;T;.;T
MetaRNN	Benign	0.0085	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	0.99	N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
Polyphen		0.13, 1.0	.;B;D;D;.;.;D;D;B;.
Vest4		0.073, 0.13, 0.13, 0.13, 0.12
MVP		0.65
MPC		0.11
ClinPred		0.033	T
GERP RS		5.0
Varity_R		0.098
gMVP		0.017

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: rs55980697; hg19: chr5-149776067; COSMIC: COSV60349840; COSMIC: COSV60349840;