NM_001371623.1:c.3G>A

Variant names:

• chr5-150357749-G-A
• rs1045446584
• NM_001371623.1:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001371623.1(TCOF1):​c.3G>A​(p.Met1?) variant causes a start lost 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCOF1 NM_001371623.1 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.24
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 13 pathogenic variants. Next in-frame start position is after 121 codons. Genomic position: 150367900. Lost 0.081 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-150357749-G-A is Pathogenic according to our data. Variant chr5-150357749-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3337661.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3G>A	p.Met1?	start_lost	Exon 1 of 27	NP_001358552.1	Q13428-3
	TCOF1	NM_001135243.2		c.3G>A	p.Met1?	start_lost	Exon 1 of 27	NP_001128715.1	Q13428-1
	TCOF1	NM_001135244.2		c.3G>A	p.Met1?	start_lost	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.3G>A	p.Met1?	start_lost	Exon 1 of 27	ENSP00000493815.1	Q13428-3
	TCOF1	ENST00000504761.6	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 26	ENSP00000421655.2	Q13428-1
	TCOF1	ENST00000323668.11	TSL:1	c.3G>A	p.Met1?	start_lost	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: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.64	D
PhyloP100		2.2
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.76
MutPred		0.97		Loss of MoRF binding (P = 0.0755)
MVP		0.97
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.18	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.92
gMVP		0.79
Mutation Taster		=4/196	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

dbSNP: rs1045446584; hg19: chr5-149737312;