19-54191871-G-T

Variant names:

• chr19-54191871-G-T
• rs201506921
• NM_001077446.4:c.394G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001077446.4(TSEN34):​c.394G>T​(p.Gly132Trp) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G132R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSEN34 NM_001077446.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.52
• Publications: 0 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: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24686843).

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.394G>T	p.Gly132Trp	missense	Exon 2 of 4	NP_001070914.1	Q9BSV6
	TSEN34	NM_001282333.2		c.394G>T	p.Gly132Trp	missense	Exon 3 of 6	NP_001269262.2	A0A590UJW4
	TSEN34	NM_001282332.2		c.394G>T	p.Gly132Trp	missense	Exon 3 of 5	NP_001269261.1	Q9BSV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	ENST00000396388.3	TSL:1 MANE Select	c.394G>T	p.Gly132Trp	missense	Exon 2 of 4	ENSP00000379671.2	Q9BSV6
	TSEN34	ENST00000302937.8	TSL:1	c.394G>T	p.Gly132Trp	missense	Exon 3 of 5	ENSP00000305524.4	Q9BSV6
	TSEN34	ENST00000396383.5	TSL:1	c.394G>T	p.Gly132Trp	missense	Exon 3 of 5	ENSP00000379667.1	Q9BSV6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.54	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.89	P
Vest4		0.43
MutPred		0.29		Gain of solvent accessibility (P = 0.0062)
MVP		0.69
MPC		0.74
ClinPred		0.68	D
GERP RS		3.3
Varity_R		0.072
gMVP		0.35
Mutation Taster		=96/4	polymorphism

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: rs201506921; hg19: chr19-54695722;