17-75516573-C-T

Position:

• chr17-75516573-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207346.3(TSEN54):​c.13C>T​(p.Pro5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,002,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.622

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07889184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN54	NM_207346.3	c.13C>T	p.Pro5Ser	missense_variant	1/11	ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11	c.13C>T	p.Pro5Ser	missense_variant	1/11	1	NM_207346.3	ENSP00000327487.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000299 AC: 3 AN: 1002284 Hom.: 0 Cov.: 38 AF XY: 0.00000636 AC XY: 3 AN XY: 471898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000106

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 01, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 5 of the TSEN54 protein (p.Pro5Ser). This variant is not present in population databases (gnomAD no frequency). 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: 325080). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

Pontoneocerebellar hypoplasia Uncertain:1

Uncertain significance, 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, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.4
DANN	Benign	0.88
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.028
Sift	Benign	0.26	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.041
MutPred		0.12		Gain of phosphorylation at P5 (P = 0.0069);
MVP		0.28
MPC		0.26
ClinPred		0.067	T
GERP RS		-0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.029
gMVP		0.29

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: rs886053394; hg19: chr17-73512654;