5-150357788-C-G

Position:

• chr5-150357788-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001371623.1(TCOF1):​c.42C>G​(p.Ile14Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,397,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I14S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.955

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-150357786-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.42C>G	p.Ile14Met	missense_variant	1/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.42C>G	p.Ile14Met	missense_variant	1/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1397466 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 689250

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 23, 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; This variant is associated with the following publications: (PMID: 22317976) -

Treacher Collins syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Oct 02, 2019

This variant has been previously identified in a mildly affected patient and an unaffected father. Another variant at this position (p.Ile14Phe) has been reported in an affected individual. The Ile14 residue is believed to be important to the formation of hydrophobic contacts between Lis1 homodimers. Although p.Ile14Met is absent from healthy population datasets, other missense variants at this and other surrounding residues are present, suggesting that missense variation in the Lis1 domain may be tolerated. Three bioinformatic tools queried predict that this substitution would be probably damaging, and the isoleucine residue at this position is evolutionarily conserved across all species assessed with the exception of the Chinese tree shrew. Due to the identification of this variant in unaffected individuals and the lack of functional evidence that this variant is deleterious, we consider the clinical significance of c.42C>G uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	.;D;.;.;.;.;.;.;.;.;.;D;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.88	D;D;D;D;.;D;D;D;D;D;D;.;D;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Benign	0.90	.;L;L;L;L;.;.;L;L;L;L;L;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	.;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		0.56, 0.66, 0.64, 0.60, 0.82, 0.63
MutPred		0.57		Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);Gain of disorder (P = 0.0127);.;
MVP		0.93
MPC		0.41
ClinPred		0.95	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.89

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: rs1581000221; hg19: chr5-149737351;