rs28941769

Variant names:

• chr5-150361196-A-G
• rs28941769
• NM_001371623.1:c.149A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001371623.1(TCOF1):​c.149A>G​(p.Tyr50Cys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y50S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.08

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-150361196-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 5-150361196-A-G is Pathogenic according to our data. Variant chr5-150361196-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3964.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-150361196-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCOF1	NM_001371623.1	c.149A>G	p.Tyr50Cys	missense_variant	Exon 2 of 27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2	c.149A>G	p.Tyr50Cys	missense_variant	Exon 2 of 27		NM_001371623.1	ENSP00000493815.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000454 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TCOF1: PS2, PM2, PS4:Moderate -

Treacher Collins syndrome 1 Pathogenic:1

Jul 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D;.;.;.;.;.;.;.;.;.;D;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;D;.;D;D;D;D;D;D;.;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.5	.;M;M;M;M;.;.;M;M;M;M;M;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.4	.;D;D;D;.;.;.;.;D;D;D;D;D;D
REVEL	Pathogenic	0.67
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		0.74, 0.76, 0.77, 0.77, 0.76
MutPred		0.75		Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);Loss of catalytic residue at I49 (P = 0.0495);.;
MVP		0.92
MPC		0.42
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.79

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: rs28941769; hg19: chr5-149740759;