19-54191403-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001077446.4(TSEN34):c.39G>A(p.Val13=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000799 in 1,549,440 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: TSEN34 NM_001077446.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.05

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-54191403-G-A is Benign according to our data. Variant chr19-54191403-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 160120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-54191403-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN34	NM_001077446.4	c.39G>A	p.Val13=	synonymous_variant	1/4	ENST00000396388.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN34	ENST00000396388.3	c.39G>A	p.Val13=	synonymous_variant	1/4	1	NM_001077446.4	P2

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 589 AN: 152198 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00100 AC: 147 AN: 146602 Hom.: 1 AF XY: 0.000812 AC XY: 64 AN XY: 78842

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.00118

Gnomad ASJ exome AF: 0.000360

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000262

Gnomad OTH exome AF: 0.000472

GnomAD4 exome AF: 0.000465 AC: 650 AN: 1397130 Hom.: 1 Cov.: 35 AF XY: 0.000422 AC XY: 291 AN XY: 689292

Gnomad4 AFR exome AF: 0.0118

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.000636

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00386 AC: 588 AN: 152310 Hom.: 3 Cov.: 32 AF XY: 0.00385 AC XY: 287 AN XY: 74468

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00170 Hom.: 1

Bravo AF: 0.00488

Asia WGS AF: 0.000579 AC: 2 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2013

- -

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
BayesDel_noAF	Benign	-0.50
Cadd	Benign	9.2
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs184898622; hg19: chr19-54695254;