rs113994150

Positions:

• chr19-54191536-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001077446.4(TSEN34):​c.172C>T​(p.Arg58Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSEN34 NM_001077446.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.67

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 19-54191536-C-T is Pathogenic according to our data. Variant chr19-54191536-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2124.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null. Variant chr19-54191536-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN34	NM_001077446.4	c.172C>T	p.Arg58Trp	missense_variant	1/4	ENST00000396388.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN34	ENST00000396388.3	c.172C>T	p.Arg58Trp	missense_variant	1/4	1	NM_001077446.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Pontocerebellar hypoplasia type 2C Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;T;.;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.60	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.7	.;.;M;.;M;M
MutationTaster	Benign	0.98	A;A;A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.0	D;N;N;.;N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.013	D;D;T;.;T;T
Sift4G	Pathogenic	0.0010	D;D;T;T;T;T
Polyphen		1.0	.;.;D;.;D;D
Vest4		0.54, 0.53, 0.54, 0.52
MutPred		0.76		Gain of catalytic residue at R58 (P = 2e-04);.;Gain of catalytic residue at R58 (P = 2e-04);.;Gain of catalytic residue at R58 (P = 2e-04);Gain of catalytic residue at R58 (P = 2e-04);
MVP		0.79
MPC		1.0
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.26
gMVP		0.77

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: rs113994150; hg19: chr19-54695387;