rs17849378

chr19-54191811-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077446.4(TSEN34):c.334C>G(p.Leu112Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,614,188 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (5 hom.)
• Consequence: TSEN34 NM_001077446.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.877

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029641092).
• BP6: Variant 19-54191811-C-G is Benign according to our data. Variant chr19-54191811-C-G is described in ClinVar as [Benign]. Clinvar id is 160119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000679 (993/1461874) while in subpopulation AFR AF= 0.018 (602/33478). AF 95% confidence interval is 0.0168. There are 5 homozygotes in gnomad4_exome. There are 424 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN34	NM_001077446.4	c.334C>G	p.Leu112Val	missense_variant	2/4	ENST00000396388.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN34	ENST00000396388.3	c.334C>G	p.Leu112Val	missense_variant	2/4	1	NM_001077446.4	P2

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 710 AN: 152196 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00145 AC: 362 AN: 249092 Hom.: 1 AF XY: 0.00102 AC XY: 138 AN XY: 135364

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000679 AC: 993 AN: 1461874 Hom.: 5 Cov.: 35 AF XY: 0.000583 AC XY: 424 AN XY: 727242

Gnomad4 AFR exome AF: 0.0180

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00363

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152314 Hom.: 6 Cov.: 32 AF XY: 0.00451 AC XY: 336 AN XY: 74484

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.00574

ESP6500AA AF: 0.0126 AC: 48

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.00167 AC: 202

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2017	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0030	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.50	N;N;N;.;N;N
REVEL	Benign	0.041
Sift	Benign	0.14	T;T;D;.;D;D
Sift4G	Benign	0.49	T;T;T;T;T;T
Polyphen		0.022	.;.;B;.;B;B
Vest4		0.16, 0.22, 0.16, 0.16
MVP		0.38
MPC		0.30
ClinPred		0.0086	T
GERP RS		2.2
Varity_R		0.099
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17849378; hg19: chr19-54695662;