rs112039991

Positions:

• chr5-150374653-G-A
• chr5-150374653-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001371623.1(TCOF1):​c.1120G>A​(p.Ala374Thr) 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. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A374S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05591449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCOF1	NM_001371623.1	c.1120G>A	p.Ala374Thr	missense_variant	9/27	ENST00000643257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCOF1	ENST00000643257.2	c.1120G>A	p.Ala374Thr	missense_variant	9/27		NM_001371623.1	P3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.41
DEOGEN2	Benign	0.075	.;T;.;.;.;.;.;.;.;.;.;T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.85	T;T;T;T;.;T;T;T;T;T;T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.056	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	.;M;.;.;M;.;.;M;M;M;M;M;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.25	.;N;N;N;.;.;.;.;N;N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.11	.;T;T;D;.;.;.;.;T;T;T;T;T
Sift4G	Benign	0.45	.;T;T;T;.;.;.;.;T;T;T;T;T
Polyphen		0.053, 0.043, 0.026, 0.074	.;B;B;B;.;.;.;.;B;B;B;B;.
Vest4		0.14, 0.15, 0.16, 0.17, 0.13, 0.17
MutPred		0.17		.;Gain of glycosylation at A374 (P = 0.0036);.;.;Gain of glycosylation at A374 (P = 0.0036);.;Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);Gain of glycosylation at A374 (P = 0.0036);
MVP		0.31
MPC		0.12
ClinPred		0.11	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.018
gMVP		0.020

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: rs112039991; hg19: chr5-149754216;