rs200434678

chr17-75522195-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_207346.3(TSEN54):c.1114G>A(p.Val372Met) variant causes a missense change. The variant allele was found at a frequency of 0.00055 in 1,550,716 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (2 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 7.09

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN54	NM_207346.3	c.1114G>A	p.Val372Met	missense_variant	8/11	ENST00000333213.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN54	ENST00000333213.11	c.1114G>A	p.Val372Met	missense_variant	8/11	1	NM_207346.3	P1

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000469 AC: 74 AN: 157756 Hom.: 0 AF XY: 0.000487 AC XY: 41 AN XY: 84130

Gnomad AFR exome AF: 0.000232

Gnomad AMR exome AF: 0.000195

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000480

Gnomad FIN exome AF: 0.000389

Gnomad NFE exome AF: 0.000791

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000561 AC: 784 AN: 1398402 Hom.: 2 Cov.: 72 AF XY: 0.000572 AC XY: 394 AN XY: 689028

Gnomad4 AFR exome AF: 0.000253

Gnomad4 AMR exome AF: 0.000272

Gnomad4 ASJ exome AF: 0.000239

Gnomad4 EAS exome AF: 0.0000558

Gnomad4 SAS exome AF: 0.000554

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.000599

Gnomad4 OTH exome AF: 0.000708

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74476

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000665 Hom.: 0

Bravo AF: 0.000400

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000232 AC: 1

ESP6500EA AF: 0.000595 AC: 5

ExAC AF: 0.000396 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 19, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 372 of the TSEN54 protein (p.Val372Met). This variant is present in population databases (rs200434678, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TSEN54-related conditions. ClinVar contains an entry for this variant (Variation ID: 160124). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSEN54 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2021

The c.1114G>A (p.V372M) alteration is located in exon 8 (coding exon 8) of the TSEN54 gene. This alteration results from a G to A substitution at nucleotide position 1114, causing the valine (V) at amino acid position 372 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Pontoneocerebellar hypoplasia Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Olivopontocerebellar hypoplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 24, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	25
Dann	Benign	0.96
DEOGEN2	Benign	0.095	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.050	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MVP		0.76
MPC		0.92
ClinPred		0.073	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.52

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: rs200434678; hg19: chr17-73518276; COSMIC: COSV99390802; COSMIC: COSV99390802;