5-150398801-G-C

Variant names:

• chr5-150398801-G-C
• rs2569062
• NM_001371623.1:c.4444-221G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001371623.1(TCOF1):​c.4444-221G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 152,124 control chromosomes in the GnomAD database, including 23,943 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.56 (23943 hom., cov: 34)
• Consequence: TCOF1 NM_001371623.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.26
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-150398801-G-C is Benign according to our data. Variant chr5-150398801-G-C is described in ClinVar as Benign. ClinVar VariationId is 1280453.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.592 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.4444-221G>C		intron	N/A	NP_001358552.1
	TCOF1	NM_001135243.2		c.4441-221G>C		intron	N/A	NP_001128715.1
	TCOF1	NM_001135244.2		c.4330-221G>C		intron	N/A	NP_001128716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.4444-221G>C		intron	N/A	ENSP00000493815.1
	TCOF1	ENST00000504761.6	TSL:1	c.4441-221G>C		intron	N/A	ENSP00000421655.2
	TCOF1	ENST00000323668.11	TSL:1	c.4210-221G>C		intron	N/A	ENSP00000325223.6

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84960 AN: 152004 Hom.: 23931 Cov.: 34

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.544

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.559 AC: 85016 AN: 152124 Hom.: 23943 Cov.: 34 AF XY: 0.556 AC XY: 41340 AN XY: 74352

African (AFR) AF: 0.544 AC: 22582 AN: 41474

American (AMR) AF: 0.474 AC: 7253 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1942 AN: 3470

East Asian (EAS) AF: 0.471 AC: 2439 AN: 5176

South Asian (SAS) AF: 0.588 AC: 2838 AN: 4826

European-Finnish (FIN) AF: 0.524 AC: 5544 AN: 10576

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.597 AC: 40606 AN: 67990

Other (OTH) AF: 0.544 AC: 1152 AN: 2116

Alfa AF: 0.469 Hom.: 1296

Bravo AF: 0.550

Asia WGS AF: 0.507 AC: 1762 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.75
DANN	Benign	0.46
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs2569062; hg19: chr5-149778364; COSMIC: COSV50532351; COSMIC: COSV50532351;