rs1554079581

Positions:

• chr5-150393451-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001371623.1(TCOF1):​c.3683C>T​(p.Ser1228Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0430

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09131625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1	c.3683C>T	p.Ser1228Phe	missense_variant	23/27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2	c.3683C>T	p.Ser1228Phe	missense_variant	23/27		NM_001371623.1	ENSP00000493815.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Treacher Collins syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;T;.;.;.;.;.;.;T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.88	D;T;T;T;.;T;T;T;.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.091	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	.;L;.;.;.;.;.;.;L;.
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.4	.;.;D;D;.;.;D;D;D;D
REVEL	Benign	0.033
Sift	Benign	0.031	.;.;D;D;.;.;D;D;D;D
Sift4G	Benign	0.63	.;T;T;T;.;.;T;T;T;T
Polyphen		0.93, 0.66	.;P;P;P;.;.;P;P;P;.
Vest4		0.14, 0.13, 0.13, 0.17, 0.15
MutPred		0.13		.;Loss of phosphorylation at S1227 (P = 0.015);.;.;.;.;.;.;Loss of phosphorylation at S1227 (P = 0.015);Loss of phosphorylation at S1227 (P = 0.015);
MVP		0.082
MPC		0.41
ClinPred		0.55	D
GERP RS		2.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.055
gMVP		0.085

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: rs1554079581; hg19: chr5-149773014; COSMIC: COSV60349980; COSMIC: COSV60349980;