5-150376181-G-C

Variant names:

• chr5-150376181-G-C
• rs2071240
• NM_001371623.1:c.1993G>C

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.1993G>C​(p.Ala665Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,614,178 control chromosomes in the GnomAD database, including 5,149 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A665S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.057 (336 hom., cov: 34)
  • Exomes 𝑓: 0.078 (4813 hom.)
• Consequence: TCOF1 NM_001371623.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.260
• Publications: 30 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
• Treacher-Collins syndrome

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017660558).
• BP6: Variant 5-150376181-G-C is Benign according to our data. Variant chr5-150376181-G-C is described in ClinVar as Benign. ClinVar VariationId is 130566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	NM_001371623.1	MANE Select	c.1993G>C	p.Ala665Pro	missense	Exon 13 of 27	NP_001358552.1
	TCOF1	NM_001135243.2		c.1993G>C	p.Ala665Pro	missense	Exon 13 of 27	NP_001128715.1
	TCOF1	NM_001135244.2		c.1993G>C	p.Ala665Pro	missense	Exon 13 of 26	NP_001128716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.1993G>C	p.Ala665Pro	missense	Exon 13 of 27	ENSP00000493815.1
	TCOF1	ENST00000504761.6	TSL:1	c.1993G>C	p.Ala665Pro	missense	Exon 13 of 26	ENSP00000421655.2
	TCOF1	ENST00000323668.11	TSL:1	c.1762G>C	p.Ala588Pro	missense	Exon 12 of 26	ENSP00000325223.6

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8715 AN: 152200 Hom.: 333 Cov.: 34

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0844

Gnomad FIN AF: 0.0704

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0818

Gnomad OTH AF: 0.0473

GnomAD2 exomes AF: 0.0694 AC: 17414 AN: 250932 AF XY: 0.0714

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.0343

Gnomad ASJ exome AF: 0.0256

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.0720

Gnomad NFE exome AF: 0.0763

Gnomad OTH exome AF: 0.0605

GnomAD4 exome AF: 0.0779 AC: 113812 AN: 1461860 Hom.: 4813 Cov.: 34 AF XY: 0.0783 AC XY: 56909 AN XY: 727226

African (AFR) AF: 0.0120 AC: 402 AN: 33480

American (AMR) AF: 0.0351 AC: 1569 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 649 AN: 26136

East Asian (EAS) AF: 0.0813 AC: 3226 AN: 39700

South Asian (SAS) AF: 0.0928 AC: 8002 AN: 86258

European-Finnish (FIN) AF: 0.0713 AC: 3808 AN: 53392

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5768

European-Non Finnish (NFE) AF: 0.0824 AC: 91659 AN: 1112008

Other (OTH) AF: 0.0717 AC: 4329 AN: 60394

GnomAD4 genome AF: 0.0573 AC: 8724 AN: 152318 Hom.: 336 Cov.: 34 AF XY: 0.0575 AC XY: 4281 AN XY: 74480

African (AFR) AF: 0.0142 AC: 592 AN: 41586

American (AMR) AF: 0.0408 AC: 624 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3470

East Asian (EAS) AF: 0.112 AC: 581 AN: 5172

South Asian (SAS) AF: 0.0842 AC: 407 AN: 4832

European-Finnish (FIN) AF: 0.0704 AC: 747 AN: 10604

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0818 AC: 5563 AN: 68020

Other (OTH) AF: 0.0510 AC: 108 AN: 2116

Alfa AF: 0.0666 Hom.: 284

Bravo AF: 0.0516

TwinsUK AF: 0.0817 AC: 303

ALSPAC AF: 0.0810 AC: 312

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0805 AC: 692

ExAC AF: 0.0691 AC: 8393

Asia WGS AF: 0.0910 AC: 316 AN: 3478

EpiCase AF: 0.0728

EpiControl AF: 0.0703

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Treacher Collins syndrome 1 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.26
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.18
Sift	Benign	0.053	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.11
MPC		0.48
ClinPred		0.019	T
GERP RS		1.9
Varity_R		0.20
gMVP		0.16
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2071240; hg19: chr5-149755744; COSMIC: COSV60345732; COSMIC: COSV60345732;