19-54190465-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000302937.8(TSEN34):c.-5+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,393,530 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: TSEN34 ENST00000302937.8 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.11

Genes affected

TSEN34 (HGNC:15506): (tRNA splicing endonuclease subunit 34) This gene encodes a catalytic subunit of the tRNA splicing endonuclease, which catalyzes the removal of introns from precursor tRNAs. The endonuclease complex is also associated with a pre-mRNA 3-prime end processing factor. A mutation in this gene results in the neurological disorder pontocerebellar hypoplasia type 2. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-54190465-G-A is Benign according to our data. Variant chr19-54190465-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 330122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN34	NM_001282333.2	c.-5+94G>A		intron_variant
TSEN34	NM_001386740.1	c.-5+94G>A		intron_variant
TSEN34	NM_024075.5	c.-5+15G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN34	ENST00000302937.8	c.-5+15G>A		intron_variant		1		P2
TSEN34	ENST00000429671.7	c.-5+94G>A		intron_variant		2		P2
TSEN34	ENST00000455798.6	c.-5+303G>A		intron_variant		2		P2

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 725 AN: 152234 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00175 AC: 2168 AN: 1241178 Hom.: 4 Cov.: 30 AF XY: 0.00180 AC XY: 1081 AN XY: 600218

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.00339

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.00314

GnomAD4 genome AF: 0.00480 AC: 732 AN: 152352 Hom.: 3 Cov.: 34 AF XY: 0.00456 AC XY: 340 AN XY: 74500

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00423 Hom.: 0

Bravo AF: 0.00530

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 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. -

Pontoneocerebellar hypoplasia Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.5
Dann	Benign	0.75

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: rs141003293; hg19: chr19-54694316;