chr5-150357822-G-A

Position:

• chr5-150357822-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP5_Moderate

The NM_001371623.1(TCOF1):​c.76G>A​(p.Ala26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A26V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-150357823-C-T is described in Lovd as [Pathogenic].
• PP5: Variant 5-150357822-G-A is Pathogenic according to our data. Variant chr5-150357822-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1311597.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.76G>A	p.Ala26Thr	missense_variant	1/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.76G>A	p.Ala26Thr	missense_variant	1/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 24, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;D;.;.;.;.;.;.;.;.;.;D;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;D;D;D;D;D;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.90	.;L;L;L;L;.;.;L;L;L;L;L;.;.
MutationTaster	Benign	0.97	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	.;D;D;D;.;.;.;.;D;D;D;D;D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	.;D;D;D;.;.;.;.;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	.;D;D;D;.;.;.;.;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;.;.;.;.;D;D;D;D;.;.
Vest4		0.52, 0.62, 0.62, 0.62, 0.67, 0.60, 0.61
MutPred		0.42		Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);Loss of ubiquitination at K31 (P = 0.0777);.;
MVP		0.93
MPC		0.28
ClinPred		0.99	D
GERP RS		3.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.55
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-149737385;