5-150357796-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001371623.1(TCOF1):c.50A>G(p.His17Arg) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.85

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-150357796-A-G is Pathogenic according to our data. Variant chr5-150357796-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 381618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150357796-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.50A>G	p.His17Arg	missense_variant	1/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.50A>G	p.His17Arg	missense_variant	1/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2016

The H17R variant in the TCOF1 gene has been reported previously as an assumed de novo variant in a patient with a clinical diagnosis of Treacher Collins syndrome (Bowman et al., 2012). The H17R variant was not observed in approximately 5200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H17R variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The H17R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Treacher Collins syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2018

For these reasons, this variant has been classified as 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 to be de novo in individuals affected with Treacher Collins syndrome (PMID: 22317976, Invitae). ClinVar contains an entry for this variant (Variation ID: 381618). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 17 of the TCOF1 protein (p.His17Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D;D;.;D;D;D;D;D;D;.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationTaster	Benign	0.88	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.69	T
Polyphen		1.0, 1.0, 1.0	.;D;D;D;.;.;.;.;D;D;D;D;.;.
Vest4		0.71, 0.85, 0.85, 0.82, 0.85, 0.76, 0.78
MutPred		0.53		Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);.;
MVP		0.99
MPC		0.32
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.94

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: rs1057521108; hg19: chr5-149737359;