19-54191402-T-C

Position:

• chr19-54191402-T-C

Variant summary

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

The NM_001077446.4(TSEN34):​c.38T>C​(p.Val13Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V13V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSEN34 NM_001077446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.678

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN34	NM_001077446.4	c.38T>C	p.Val13Ala	missense_variant	1/4	ENST00000396388.3	NP_001070914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN34	ENST00000396388.3	c.38T>C	p.Val13Ala	missense_variant	1/4	1	NM_001077446.4	ENSP00000379671	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.38T>C (p.V13A) alteration is located in exon 2 (coding exon 1) of the TSEN34 gene. This alteration results from a T to C substitution at nucleotide position 38, causing the valine (V) at amino acid position 13 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;T;.;T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.47	N
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Uncertain	2.5	.;.;M;.;M;M
MutationTaster	Benign	0.90	D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.0	D;D;D;.;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;D;D;.;D;D
Sift4G	Uncertain	0.020	D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;D;D
Vest4		0.51, 0.40, 0.36
MutPred		0.48		Loss of stability (P = 0.0489);.;Loss of stability (P = 0.0489);.;Loss of stability (P = 0.0489);Loss of stability (P = 0.0489);
MVP		0.66
MPC		0.98
ClinPred		0.95	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-54695253;