5-150361164-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001371623.1(TCOF1):c.117C>A(p.Phe39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.162963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.117C>A	p.Phe39Leu	missense_variant	2/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.117C>A	p.Phe39Leu	missense_variant	2/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Treacher Collins syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.0092	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	18
Dann	Benign	0.97
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.73
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T;T;T;T;.;T;T;T;T;T;T;.;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.58	T
Polyphen		0.14, 0.11, 0.12	.;B;B;B;.;.;.;.;B;B;B;B;.;.
Vest4		0.47, 0.36, 0.36, 0.35, 0.33, 0.35
MutPred		0.59		Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);Gain of ubiquitination at K37 (P = 0.0817);.;
MVP		0.48
MPC		0.093
ClinPred		0.22	T
GERP RS		3.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.8
Varity_R		0.19
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1759991869; hg19: chr5-149740727;