rs75583421

Positions:

• chr5-150375799-G-A

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.1783G>A​(p.Val595Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00956 in 1,614,248 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (10 hom., cov: 34)
  • Exomes 𝑓: 0.0097 (92 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.390

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=0.005758971).
• BP6: Variant 5-150375799-G-A is Benign according to our data. Variant chr5-150375799-G-A is described in ClinVar as [Benign]. Clinvar id is 352213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150375799-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00784 (1194/152362) while in subpopulation NFE AF= 0.0111 (756/68028). AF 95% confidence interval is 0.0105. There are 10 homozygotes in gnomad4. There are 603 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1194 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.1783G>A	p.Val595Ile	missense_variant	12/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.1783G>A	p.Val595Ile	missense_variant	12/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1194 AN: 152244 Hom.: 10 Cov.: 34

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00746 AC: 1875 AN: 251374 Hom.: 10 AF XY: 0.00741 AC XY: 1007 AN XY: 135864

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00973 AC: 14231 AN: 1461886 Hom.: 92 Cov.: 35 AF XY: 0.00960 AC XY: 6983 AN XY: 727242

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.00937

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.0135

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00808

GnomAD4 genome AF: 0.00784 AC: 1194 AN: 152362 Hom.: 10 Cov.: 34 AF XY: 0.00809 AC XY: 603 AN XY: 74512

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0100 Hom.: 8

Bravo AF: 0.00650

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0117 AC: 101

ExAC AF: 0.00765 AC: 929

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.00942

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2020	This variant is associated with the following publications: (PMID: 28065470) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TCOF1: BP4, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 13, 2017

- -

Treacher Collins syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Uncertain	1.0
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.87	D;T;D;D;.;D;T;T;D;T;.;T
MetaRNN	Benign	0.0058	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
Polyphen		0.95, 0.22	.;P;B;B;.;.;.;B;B;B;P;.
Vest4		0.11, 0.080, 0.074, 0.12, 0.081, 0.14
MVP		0.43
MPC		0.38
ClinPred		0.020	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.047

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: rs75583421; hg19: chr5-149755362; COSMIC: COSV99059926; COSMIC: COSV99059926;