rs73270831

Positions:

• chr5-150361209-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001371623.1(TCOF1):​c.162A>G​(p.Gln54=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,118 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: TCOF1 NM_001371623.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003788
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.21

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-150361209-A-G is Benign according to our data. Variant chr5-150361209-A-G is described in ClinVar as [Benign]. Clinvar id is 130563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150361209-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00932 (1419/152278) while in subpopulation AFR AF= 0.0308 (1281/41540). AF 95% confidence interval is 0.0294. There are 23 homozygotes in gnomad4. There are 642 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1419 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1	c.162A>G	p.Gln54=	splice_region_variant, synonymous_variant	2/27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2	c.162A>G	p.Gln54=	splice_region_variant, synonymous_variant	2/27		NM_001371623.1	ENSP00000493815	P3

Frequencies

GnomAD3 genomes AF: 0.00931 AC: 1417 AN: 152160 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00641

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: 0.000279

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00249 AC: 627 AN: 251480 Hom.: 7 AF XY: 0.00179 AC XY: 243 AN XY: 135922

Gnomad AFR exome AF: 0.0308

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00113 AC: 1650 AN: 1461840 Hom.: 25 Cov.: 31 AF XY: 0.00100 AC XY: 727 AN XY: 727222

Gnomad4 AFR exome AF: 0.0323

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000232

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00932 AC: 1419 AN: 152278 Hom.: 23 Cov.: 32 AF XY: 0.00862 AC XY: 642 AN XY: 74456

Gnomad4 AFR AF: 0.0308

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00450 Hom.: 7

Bravo AF: 0.0111

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 20, 2020

This variant is associated with the following publications: (PMID: 12210332) -

Treacher Collins syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00038
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs73270831; hg19: chr5-149740772;