chr19-54191536-C-T

Variant names:

• chr19-54191536-C-T
• rs113994150
• NM_001077446.4:c.172C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 8 publications found

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]

TSEN34 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 2C

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 2124.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077446.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	NM_001077446.4	MANE Select	c.172C>T	p.Arg58Trp	missense	Exon 1 of 4	NP_001070914.1
	TSEN34	NM_001282333.2		c.172C>T	p.Arg58Trp	missense	Exon 2 of 6	NP_001269262.2
	TSEN34	NM_001282332.2		c.172C>T	p.Arg58Trp	missense	Exon 2 of 5	NP_001269261.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	ENST00000396388.3	TSL:1 MANE Select	c.172C>T	p.Arg58Trp	missense	Exon 1 of 4	ENSP00000379671.2
	TSEN34	ENST00000302937.8	TSL:1	c.172C>T	p.Arg58Trp	missense	Exon 2 of 5	ENSP00000305524.4
	TSEN34	ENST00000396383.5	TSL:1	c.172C>T	p.Arg58Trp	missense	Exon 2 of 5	ENSP00000379667.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pontocerebellar hypoplasia type 2C (2)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.013	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.76		Gain of catalytic residue at R58 (P = 2e-04)
MVP		0.79
MPC		1.0
ClinPred		0.99	D
GERP RS		4.1
PromoterAI		-0.035	Neutral
Varity_R		0.26
gMVP		0.77
Mutation Taster		=26/74	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs113994150; hg19: chr19-54695387;