chr5-150357835-T-G

Position:

• chr5-150357835-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001371623.1(TCOF1):​c.89T>G​(p.Val30Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.78

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-150357835-T-G is Pathogenic according to our data. Variant chr5-150357835-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 960386.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.89T>G	p.Val30Gly	missense_variant	1/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.89T>G	p.Val30Gly	missense_variant	1/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Treacher Collins syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2019

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) affected with Treacher Collins syndrome (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with glycine at codon 30 of the TCOF1 protein (p.Val30Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	.;D;.;.;.;.;.;.;.;.;.;D;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.73	T;T;T;T;.;T;T;T;T;T;T;.;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.69	.;N;N;N;N;.;.;N;N;N;N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.6	.;D;D;D;.;.;.;.;D;D;D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	.;D;D;D;.;.;.;.;D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	.;D;D;D;.;.;.;.;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;.;.;.;.;D;D;D;D;.;.
Vest4		0.37, 0.51, 0.51, 0.52, 0.48, 0.42, 0.52
MutPred		0.43		Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);Loss of stability (P = 0.0151);.;
MVP		0.89
MPC		0.30
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.82
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1758963105; hg19: chr5-149737398;