rs15251

Variant names:

• chr5-150396669-C-T
• rs15251
• NM_001371623.1:c.4172C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001371623.1(TCOF1):​c.4172C>T​(p.Ala1391Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,610,116 control chromosomes in the GnomAD database, including 58,602 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1391T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.22 (4239 hom., cov: 31)
  • Exomes 𝑓: 0.27 (54363 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.56
• Publications: 53 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038337708).
• BP6: Variant 5-150396669-C-T is Benign according to our data. Variant chr5-150396669-C-T is described in ClinVar as Benign. ClinVar VariationId is 130574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

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.4172C>T	p.Ala1391Val	missense	Exon 24 of 27	NP_001358552.1	Q13428-3
	TCOF1	NM_001135243.2		c.4169C>T	p.Ala1390Val	missense	Exon 24 of 27	NP_001128715.1	Q13428-1
	TCOF1	NM_001135244.2		c.4058C>T	p.Ala1353Val	missense	Exon 23 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.4172C>T	p.Ala1391Val	missense	Exon 24 of 27	ENSP00000493815.1	Q13428-3
	TCOF1	ENST00000504761.6	TSL:1	c.4169C>T	p.Ala1390Val	missense	Exon 24 of 26	ENSP00000421655.2	Q13428-1
	TCOF1	ENST00000323668.11	TSL:1	c.3938C>T	p.Ala1313Val	missense	Exon 23 of 26	ENSP00000325223.6	Q13428-2

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33216 AN: 151734 Hom.: 4232 Cov.: 31

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.364

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.259 AC: 63514 AN: 245036 AF XY: 0.270

Gnomad AFR exome AF: 0.0752

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.244

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.268 AC: 391363 AN: 1458264 Hom.: 54363 Cov.: 38 AF XY: 0.273 AC XY: 197577 AN XY: 724978

African (AFR) AF: 0.0743 AC: 2484 AN: 33452

American (AMR) AF: 0.235 AC: 10361 AN: 44128

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 9642 AN: 26024

East Asian (EAS) AF: 0.185 AC: 7339 AN: 39642

South Asian (SAS) AF: 0.361 AC: 30999 AN: 85830

European-Finnish (FIN) AF: 0.250 AC: 13230 AN: 52994

Middle Eastern (MID) AF: 0.311 AC: 1791 AN: 5750

European-Non Finnish (NFE) AF: 0.269 AC: 299137 AN: 1110152

Other (OTH) AF: 0.272 AC: 16380 AN: 60292

GnomAD4 genome AF: 0.219 AC: 33228 AN: 151852 Hom.: 4239 Cov.: 31 AF XY: 0.220 AC XY: 16340 AN XY: 74166

African (AFR) AF: 0.0801 AC: 3318 AN: 41412

American (AMR) AF: 0.246 AC: 3761 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1317 AN: 3466

East Asian (EAS) AF: 0.193 AC: 988 AN: 5128

South Asian (SAS) AF: 0.364 AC: 1745 AN: 4800

European-Finnish (FIN) AF: 0.241 AC: 2544 AN: 10550

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18695 AN: 67904

Other (OTH) AF: 0.236 AC: 498 AN: 2108

Alfa AF: 0.261 Hom.: 16040

Bravo AF: 0.208

TwinsUK AF: 0.264 AC: 979

ALSPAC AF: 0.275 AC: 1059

ESP6500AA AF: 0.0876 AC: 386

ESP6500EA AF: 0.273 AC: 2349

ExAC AF: 0.256 AC: 31068

Asia WGS AF: 0.260 AC: 902 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	not provided (1)
-	-	1	Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.6
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.15
Sift	Uncertain	0.013	D
Sift4G	Benign	0.062	T
Polyphen		0.90	P
Vest4		0.029
MPC		0.23
ClinPred		0.027	T
GERP RS		2.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.052
gMVP		0.0035
Mutation Taster		=99/1	polymorphism (auto)

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: rs15251; hg19: chr5-149776232; COSMIC: COSV60347011; COSMIC: COSV60347011;