rs144327167

chr5-150374331-G-Achr5-150374331-G-C

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.1028G>A(p.Ser343Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,571,546 control chromosomes in the GnomAD database, including 11 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S343S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (11 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.73

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=0.006667733).
• BP6: Variant 5-150374331-G-A is Benign according to our data. Variant chr5-150374331-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 209020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150374331-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00186 (283/152070) while in subpopulation NFE AF= 0.00229 (156/67980). AF 95% confidence interval is 0.002. There are 0 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 283 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.1028G>A	p.Ser343Asn	missense_variant	8/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.1028G>A	p.Ser343Asn	missense_variant	8/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 151952 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00773

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00236 AC: 426 AN: 180492 Hom.: 3 AF XY: 0.00238 AC XY: 229 AN XY: 96090

Gnomad AFR exome AF: 0.000470

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.0000764

Gnomad SAS exome AF: 0.00169

Gnomad FIN exome AF: 0.00822

Gnomad NFE exome AF: 0.00256

Gnomad OTH exome AF: 0.00202

GnomAD4 exome AF: 0.00217 AC: 3078 AN: 1419476 Hom.: 11 Cov.: 32 AF XY: 0.00222 AC XY: 1562 AN XY: 702388

Gnomad4 AFR exome AF: 0.000186

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.000118

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.00703

Gnomad4 NFE exome AF: 0.00221

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00186 AC: 283 AN: 152070 Hom.: 0 Cov.: 33 AF XY: 0.00218 AC XY: 162 AN XY: 74318

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00773

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00225 Hom.: 1

Bravo AF: 0.00136

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00183 AC: 218

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2019	This variant is associated with the following publications: (PMID: 28419064, 30245029, 28065470, 15340364) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	TCOF1: BP4, BS1, BS2 -

Treacher Collins syndrome 1 Benign:2

Likely benign, no assertion criteria provided	not provided	Genetics Laboratories, Oxford Radcliffe Hospitals NHS Trust	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	23
Dann	Uncertain	0.98
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.70	T;T;T;T;.;T;T;T;T;T;.;T
MetaRNN	Benign	0.0067	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
Polyphen		0.99, 0.21, 0.98, 0.54	.;D;B;B;.;.;.;D;P;D;D;.
Vest4		0.37, 0.49, 0.49, 0.47, 0.46
MVP		0.63
MPC		0.43
ClinPred		0.045	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.12

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: rs144327167; hg19: chr5-149753894;