rs144662042

chr17-75524299-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_207346.3(TSEN54):c.1468C>T(p.Arg490Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,614,166 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R490Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (31 hom., cov: 32)
  • Exomes 𝑓: 0.015 (233 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.43

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005048424).
• BP6: Variant 17-75524299-C-T is Benign according to our data. Variant chr17-75524299-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 160130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75524299-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.013 (1974/152324) while in subpopulation NFE AF= 0.0192 (1305/68034). AF 95% confidence interval is 0.0183. There are 31 homozygotes in gnomad4. There are 990 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN54	NM_207346.3	c.1468C>T	p.Arg490Trp	missense_variant	11/11	ENST00000333213.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN54	ENST00000333213.11	c.1468C>T	p.Arg490Trp	missense_variant	11/11	1	NM_207346.3	P1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1974 AN: 152206 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.0123 AC: 3096 AN: 251452 Hom.: 32 AF XY: 0.0124 AC XY: 1684 AN XY: 135912

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.0332

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0153 AC: 22301 AN: 1461842 Hom.: 233 Cov.: 31 AF XY: 0.0150 AC XY: 10932 AN XY: 727224

Gnomad4 AFR exome AF: 0.00284

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00319

Gnomad4 FIN exome AF: 0.0346

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0130 AC: 1974 AN: 152324 Hom.: 31 Cov.: 32 AF XY: 0.0133 AC XY: 990 AN XY: 74472

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0329

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0161 Hom.: 29

Bravo AF: 0.0102

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0171 AC: 147

ExAC AF: 0.0132 AC: 1605

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2016	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 02, 2018	- -

Pontoneocerebellar hypoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.78	N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.19
Sift	Benign	0.034	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.14
MPC		0.86
ClinPred		0.029	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144662042; hg19: chr17-73520380; COSMIC: COSV51355948; COSMIC: COSV51355948;