5-150357831-G-C

Position:

• chr5-150357831-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001371623.1(TCOF1):​c.85G>C​(p.Glu29Gln) 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: 32)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32662654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.85G>C	p.Glu29Gln	missense_variant	1/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.85G>C	p.Glu29Gln	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

Treacher Collins syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Treacher Collins syndrome 1 (MIM#154500). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. While penetrance for Treacher Collins syndrome 1 (MIM#154500) is high, reduced penetrance has been reported for TCOF1 (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant inter and intra familial variability has been reported (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;D;.;.;.;.;.;.;.;.;.;D;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.81	.;L;L;L;L;.;.;L;L;L;L;L;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	.;D;D;D;.;.;.;.;D;N;N;D;N;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	.;D;D;D;.;.;.;.;D;D;D;D;D;.
Sift4G	Uncertain	0.020	.;D;D;D;.;.;.;.;D;T;D;D;D;T
Polyphen		0.92, 0.97, 0.95, 0.98	.;P;D;D;.;.;.;.;P;D;P;P;.;.
Vest4		0.17, 0.19, 0.20, 0.22, 0.35, 0.24, 0.22
MutPred		0.28		Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);.;
MVP		0.60
MPC		0.19
ClinPred		0.80	D
GERP RS		4.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.69
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-149737394;