rs2071239

Variant names:

• chr5-150375858-A-G
• rs2071239
• NM_001371623.1:c.1842A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001371623.1(TCOF1):​c.1842A>G​(p.Ser614Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,614,034 control chromosomes in the GnomAD database, including 20,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2638 hom., cov: 34)
  • Exomes 𝑓: 0.15 (18295 hom.)
• Consequence: TCOF1 NM_001371623.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.12
• Publications: 22 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-150375858-A-G is Benign according to our data. Variant chr5-150375858-A-G is described in ClinVar as Benign. ClinVar VariationId is 130565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.26 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	NM_001371623.1	MANE Select	c.1842A>G	p.Ser614Ser	synonymous	Exon 12 of 27	NP_001358552.1	Q13428-3
	TCOF1	NM_001135243.2		c.1842A>G	p.Ser614Ser	synonymous	Exon 12 of 27	NP_001128715.1	Q13428-1
	TCOF1	NM_001135244.2		c.1842A>G	p.Ser614Ser	synonymous	Exon 12 of 26	NP_001128716.1	Q13428-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCOF1	ENST00000643257.2	MANE Select	c.1842A>G	p.Ser614Ser	synonymous	Exon 12 of 27	ENSP00000493815.1	Q13428-3
	TCOF1	ENST00000504761.6	TSL:1	c.1842A>G	p.Ser614Ser	synonymous	Exon 12 of 26	ENSP00000421655.2	Q13428-1
	TCOF1	ENST00000323668.11	TSL:1	c.1611A>G	p.Ser537Ser	synonymous	Exon 11 of 26	ENSP00000325223.6	Q13428-2

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26894 AN: 152064 Hom.: 2633 Cov.: 34

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.143 AC: 36033 AN: 251288 AF XY: 0.142

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.0844

Gnomad ASJ exome AF: 0.0619

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.155 AC: 225866 AN: 1461852 Hom.: 18295 Cov.: 35 AF XY: 0.154 AC XY: 111754 AN XY: 727230

African (AFR) AF: 0.270 AC: 9023 AN: 33478

American (AMR) AF: 0.0874 AC: 3908 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 1567 AN: 26136

East Asian (EAS) AF: 0.0905 AC: 3592 AN: 39700

South Asian (SAS) AF: 0.139 AC: 11982 AN: 86258

European-Finnish (FIN) AF: 0.137 AC: 7339 AN: 53406

Middle Eastern (MID) AF: 0.109 AC: 627 AN: 5768

European-Non Finnish (NFE) AF: 0.161 AC: 178572 AN: 1111990

Other (OTH) AF: 0.153 AC: 9256 AN: 60392

GnomAD4 genome AF: 0.177 AC: 26941 AN: 152182 Hom.: 2638 Cov.: 34 AF XY: 0.174 AC XY: 12949 AN XY: 74406

African (AFR) AF: 0.264 AC: 10972 AN: 41528

American (AMR) AF: 0.119 AC: 1828 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3470

East Asian (EAS) AF: 0.127 AC: 654 AN: 5152

South Asian (SAS) AF: 0.128 AC: 617 AN: 4828

European-Finnish (FIN) AF: 0.137 AC: 1449 AN: 10614

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10762 AN: 67972

Other (OTH) AF: 0.160 AC: 338 AN: 2112

Alfa AF: 0.159 Hom.: 9624

Bravo AF: 0.179

Asia WGS AF: 0.156 AC: 540 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.147

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)
-	-	1	Treacher Collins syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.23
DANN	Benign	0.39
PhyloP100		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs2071239; hg19: chr5-149755421; COSMIC: COSV60345705; COSMIC: COSV60345705;