rs6501818

Positions:

• chr17-75517208-C-G
• chr17-75517208-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_207346.3(TSEN54):​c.333C>G​(p.Arg111Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,605,396 control chromosomes in the GnomAD database, including 17,701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3394 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14307 hom.)
• Consequence: TSEN54 NM_207346.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.683

Genes affected

TSEN54 (HGNC:27561): (tRNA splicing endonuclease subunit 54) This gene encodes a subunit of the tRNA splicing endonuclease complex, which catalyzes the removal of introns from precursor tRNAs. The complex is also implicated in pre-mRNA 3-prime end processing. Mutations in this gene result in pontocerebellar hypoplasia type 2.[provided by RefSeq, Oct 2009]

TSEN54 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 17-75517208-C-G is Benign according to our data. Variant chr17-75517208-C-G is described in ClinVar as [Benign]. Clinvar id is 137756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75517208-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.683 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN54	NM_207346.3	c.333C>G	p.Arg111Arg	synonymous_variant	4/11	ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11	c.333C>G	p.Arg111Arg	synonymous_variant	4/11	1	NM_207346.3	ENSP00000327487.6

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28132 AN: 152050 Hom.: 3384 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0205

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.179

GnomAD3 exomes AF: 0.126 AC: 29464 AN: 233248 Hom.: 2276 AF XY: 0.124 AC XY: 15662 AN XY: 126620

Gnomad AFR exome AF: 0.331

Gnomad AMR exome AF: 0.0835

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0173

Gnomad SAS exome AF: 0.0966

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.134 AC: 194522 AN: 1453228 Hom.: 14307 Cov.: 40 AF XY: 0.132 AC XY: 95593 AN XY: 722030

Gnomad4 AFR exome AF: 0.349

Gnomad4 AMR exome AF: 0.0871

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.0179

Gnomad4 SAS exome AF: 0.0986

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.185 AC: 28179 AN: 152168 Hom.: 3394 Cov.: 32 AF XY: 0.181 AC XY: 13497 AN XY: 74398

Gnomad4 AFR AF: 0.337

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.0201

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.178

Alfa AF: 0.156 Hom.: 701

Bravo AF: 0.192

Asia WGS AF: 0.0890 AC: 312 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Pontoneocerebellar hypoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.4
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs6501818; hg19: chr17-73513289;