rs797046053

Variant names:

• chr19-54191745-C-G
• rs797046053
• NM_001077446.4:c.268C>G

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.268C>G​(p.Gln90Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TSEN34 NM_001077446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24
• 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: 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1308755).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	NM_001077446.4	MANE Select	c.268C>G	p.Gln90Glu	missense	Exon 2 of 4	NP_001070914.1
	TSEN34	NM_001282333.2		c.268C>G	p.Gln90Glu	missense	Exon 3 of 6	NP_001269262.2
	TSEN34	NM_001282332.2		c.268C>G	p.Gln90Glu	missense	Exon 3 of 5	NP_001269261.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN34	ENST00000396388.3	TSL:1 MANE Select	c.268C>G	p.Gln90Glu	missense	Exon 2 of 4	ENSP00000379671.2
	TSEN34	ENST00000302937.8	TSL:1	c.268C>G	p.Gln90Glu	missense	Exon 3 of 5	ENSP00000305524.4
	TSEN34	ENST00000396383.5	TSL:1	c.268C>G	p.Gln90Glu	missense	Exon 3 of 5	ENSP00000379667.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248094 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461794 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.43	N
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.098
Sift	Benign	0.23	T
Sift4G	Benign	0.30	T
Polyphen		0.67	P
Vest4		0.47
MutPred		0.25		Loss of MoRF binding (P = 0.0798)
MVP		0.57
MPC		0.81
ClinPred		0.63	D
GERP RS		4.4
PromoterAI		0.065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.42
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs797046053; hg19: chr19-54695596;