chr5-150374871-G-C

Variant names:

• chr5-150374871-G-C
• rs143713714
• NM_001371623.1:c.1278+60G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001371623.1(TCOF1):​c.1278+60G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0092 in 1,610,052 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (14 hom., cov: 34)
  • Exomes 𝑓: 0.0093 (91 hom.)
• Consequence: TCOF1 NM_001371623.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.136
• 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: 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=-0.84).
• BP6: Variant 5-150374871-G-C is Benign according to our data. Variant chr5-150374871-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 209026.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00825 (1245/150848) while in subpopulation AMR AF = 0.0169 (257/15208). AF 95% confidence interval is 0.0152. There are 14 homozygotes in GnomAd4. There are 588 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1245 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCOF1	NM_001371623.1	c.1278+60G>C		intron_variant	Intron 9 of 26	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2	c.1278+60G>C		intron_variant	Intron 9 of 26		NM_001371623.1	ENSP00000493815.1

Frequencies

GnomAD3 genomes AF: 0.00825 AC: 1244 AN: 150714 Hom.: 14 Cov.: 34

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00778

Gnomad FIN AF: 0.00450

Gnomad MID AF: 0.0137

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0160

GnomAD4 exome AF: 0.00929 AC: 13562 AN: 1459204 Hom.: 91 Cov.: 33 AF XY: 0.00939 AC XY: 6815 AN XY: 725834

African (AFR) AF: 0.00144 AC: 48 AN: 33440

American (AMR) AF: 0.00743 AC: 328 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 598 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00802 AC: 691 AN: 86116

European-Finnish (FIN) AF: 0.00413 AC: 220 AN: 53262

Middle Eastern (MID) AF: 0.0255 AC: 147 AN: 5768

European-Non Finnish (NFE) AF: 0.00984 AC: 10926 AN: 1110482

Other (OTH) AF: 0.0100 AC: 604 AN: 60296

GnomAD4 genome AF: 0.00825 AC: 1245 AN: 150848 Hom.: 14 Cov.: 34 AF XY: 0.00798 AC XY: 588 AN XY: 73670

African (AFR) AF: 0.00171 AC: 70 AN: 40958

American (AMR) AF: 0.0169 AC: 257 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5014

South Asian (SAS) AF: 0.00778 AC: 37 AN: 4756

European-Finnish (FIN) AF: 0.00450 AC: 47 AN: 10444

Middle Eastern (MID) AF: 0.0144 AC: 4 AN: 278

European-Non Finnish (NFE) AF: 0.0105 AC: 713 AN: 67736

Other (OTH) AF: 0.0158 AC: 33 AN: 2086

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.00820

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Treacher Collins syndrome 1 Benign:1

-

Genetics Laboratories, Oxford Radcliffe Hospitals NHS Trust

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.58
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

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: rs143713714; hg19: chr5-149754434;