rs587784480

Variant names:

• chr17-75522045-C-G
• rs587784480
• NM_207346.3:c.964C>G

Variant summary

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

The NM_207346.3(TSEN54):​c.964C>G​(p.Leu322Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,437,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.866

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=0.17577377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSEN54	NM_207346.3	c.964C>G	p.Leu322Val	missense_variant	Exon 8 of 11	ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11	c.964C>G	p.Leu322Val	missense_variant	Exon 8 of 11	1	NM_207346.3	ENSP00000327487.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000986 AC: 2 AN: 202826 Hom.: 0 AF XY: 0.00000909 AC XY: 1 AN XY: 109954

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000658

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1437688 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 713184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000481

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 322 of the TSEN54 protein (p.Leu322Val). This variant is present in population databases (rs587784480, gnomAD 0.007%). 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: 160140). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

Olivopontocerebellar hypoplasia Uncertain:1

Dec 23, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.84
DEOGEN2	Benign	0.030	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.22
Sift	Benign	0.065	T
Sift4G	Benign	0.081	T
Polyphen		0.98	D
Vest4		0.25
MutPred		0.20		Loss of glycosylation at P320 (P = 0.0923);
MVP		0.78
MPC		0.92
ClinPred		0.45	T
GERP RS		2.9
Varity_R		0.14
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587784480; hg19: chr17-73518126;