5-150357905-AGCGGCCC-AGCGGCCCGCGGCCC

Variant names:

• chr5-150357905-A-AGCGGCCC
• rs151344564
• NM_001371623.1:c.108+62_108+68dupGCCCGCG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001371623.1(TCOF1):​c.108+62_108+68dupGCCCGCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,517,828 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TCOF1 NM_001371623.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.160
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 20 AD gene.

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.108+62_108+68dupGCCCGCG		intron	N/A	NP_001358552.1	Q13428-3
	TCOF1	NM_001135243.2		c.108+62_108+68dupGCCCGCG		intron	N/A	NP_001128715.1	Q13428-1
	TCOF1	NM_001135244.2		c.108+62_108+68dupGCCCGCG		intron	N/A	NP_001128716.1	Q13428-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.108+51_108+52insGCGGCCC		intron	N/A	ENSP00000493815.1	Q13428-3
	TCOF1	ENST00000504761.6	TSL:1	c.108+51_108+52insGCGGCCC		intron	N/A	ENSP00000421655.2	Q13428-1
	TCOF1	ENST00000323668.11	TSL:1	c.108+51_108+52insGCGGCCC		intron	N/A	ENSP00000325223.6	Q13428-2

Frequencies

GnomAD3 genomes AF: 0.0000143 AC: 2 AN: 139764 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000160

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000361 AC: 5 AN: 138534 AF XY: 0.0000401

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000943

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000145 AC: 20 AN: 1378064 Hom.: 0 Cov.: 28 AF XY: 0.0000118 AC XY: 8 AN XY: 679972

African (AFR) AF: 0.00 AC: 0 AN: 30508

American (AMR) AF: 0.000142 AC: 5 AN: 35314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24826

East Asian (EAS) AF: 0.0000284 AC: 1 AN: 35198

South Asian (SAS) AF: 0.0000255 AC: 2 AN: 78476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44562

Middle Eastern (MID) AF: 0.000229 AC: 1 AN: 4372

European-Non Finnish (NFE) AF: 0.00000843 AC: 9 AN: 1067656

Other (OTH) AF: 0.0000350 AC: 2 AN: 57152

GnomAD4 genome AF: 0.0000143 AC: 2 AN: 139764 Hom.: 0 Cov.: 32 AF XY: 0.0000145 AC XY: 1 AN XY: 68874

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000266 AC: 1 AN: 37576

American (AMR) AF: 0.00 AC: 0 AN: 14468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3264

East Asian (EAS) AF: 0.00 AC: 0 AN: 4544

South Asian (SAS) AF: 0.00 AC: 0 AN: 4420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 246

European-Non Finnish (NFE) AF: 0.0000160 AC: 1 AN: 62310

Other (OTH) AF: 0.00 AC: 0 AN: 1878

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs151344564; hg19: chr5-149737468;