rs2748222

Variant names:

• chr5-150385777-A-G
• rs2748222
• NM_001371623.1:c.2860-2125A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001371623.1(TCOF1):​c.2860-2125A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 151,960 control chromosomes in the GnomAD database, including 12,583 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (12583 hom., cov: 32)
• Consequence: TCOF1 NM_001371623.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.328
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCOF1	NM_001371623.1	c.2860-2125A>G		intron_variant	Intron 17 of 26	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2	c.2860-2125A>G		intron_variant	Intron 17 of 26		NM_001371623.1	ENSP00000493815.1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61332 AN: 151840 Hom.: 12586 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.405

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

GnomAD4 genome AF: 0.404 AC: 61344 AN: 151960 Hom.: 12583 Cov.: 32 AF XY: 0.403 AC XY: 29925 AN XY: 74250

African (AFR) AF: 0.343 AC: 14206 AN: 41418

American (AMR) AF: 0.364 AC: 5557 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1753 AN: 3470

East Asian (EAS) AF: 0.430 AC: 2221 AN: 5164

South Asian (SAS) AF: 0.477 AC: 2297 AN: 4816

European-Finnish (FIN) AF: 0.387 AC: 4088 AN: 10558

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29841 AN: 67936

Other (OTH) AF: 0.402 AC: 847 AN: 2106

Alfa AF: 0.417 Hom.: 1719

Bravo AF: 0.396

Asia WGS AF: 0.397 AC: 1381 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.43
PhyloP100		-0.33
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: rs2748222; hg19: chr5-149765340; COSMIC: COSV60346975; COSMIC: COSV60346975;