5-150392152-G-A

Variant names:

• chr5-150392152-G-A
• NM_001371623.1:c.3493G>A
• TCOF1 p.Gly1165Arg

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001371623.1(TCOF1):​c.3493G>A​(p.Gly1165Arg) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.516
• 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Treacher-Collins syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027722657).

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.3493G>A	p.Gly1165Arg	missense	Exon 21 of 27	NP_001358552.1	Q13428-3
	TCOF1	NM_001135243.2		c.3493G>A	p.Gly1165Arg	missense	Exon 21 of 27	NP_001128715.1	Q13428-1
	TCOF1	NM_001135244.2		c.3379G>A	p.Gly1127Arg	missense	Exon 20 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.3493G>A	p.Gly1165Arg	missense	Exon 21 of 27	ENSP00000493815.1	Q13428-3
	TCOF1	ENST00000504761.6	TSL:1	c.3493G>A	p.Gly1165Arg	missense	Exon 21 of 26	ENSP00000421655.2	Q13428-1
	TCOF1	ENST00000323668.11	TSL:1	c.3262G>A	p.Gly1088Arg	missense	Exon 20 of 26	ENSP00000325223.6	Q13428-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.33
DANN	Benign	0.55
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.52
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.079
Sift	Benign	0.77	T
Sift4G	Benign	0.14	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.032
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-149771715;