NM_001371623.1:c.53T>C

Variant names:

• chr5-150357799-T-C
• NM_001371623.1:c.53T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001371623.1(TCOF1):​c.53T>C​(p.Leu18Pro) 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 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: 2.31
• Publications: 0 publications found

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]

TCOF1 Gene-Disease associations (from GenCC):

• Treacher Collins syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• Treacher-Collins syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001371623.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371623.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	NM_001371623.1	MANE Select	c.53T>C	p.Leu18Pro	missense	Exon 1 of 27	NP_001358552.1	Q13428-3
	TCOF1	NM_001135243.2		c.53T>C	p.Leu18Pro	missense	Exon 1 of 27	NP_001128715.1	Q13428-1
	TCOF1	NM_001135244.2		c.53T>C	p.Leu18Pro	missense	Exon 1 of 26	NP_001128716.1	Q13428-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.53T>C	p.Leu18Pro	missense	Exon 1 of 27	ENSP00000493815.1	Q13428-3
	TCOF1	ENST00000504761.6	TSL:1	c.53T>C	p.Leu18Pro	missense	Exon 1 of 26	ENSP00000421655.2	Q13428-1
	TCOF1	ENST00000323668.11	TSL:1	c.53T>C	p.Leu18Pro	missense	Exon 1 of 26	ENSP00000325223.6	Q13428-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.90	L
PhyloP100		2.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.70		Loss of helix (P = 0.0072)
MVP		0.99
MPC		0.16
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.92
gMVP		0.99
Mutation Taster		=16/84	disease causing

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

Other links and lift over

hg19: chr5-149737362;