Genetic Variant NM_001077446.4:c.5T>C (chr19-54191369-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001077446.4(TSEN34):c.5T>C(p.Leu2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,549,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TSEN34
NM_001077446.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.820

Publications

0 publications found

Variant links:

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

TSEN34 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSEN34	NM_001077446.4	MANE Select	c.5T>C	p.Leu2Pro	missense	Exon 1 of 4	NP_001070914.1	Q9BSV6
TSEN34	NM_001282333.2		c.5T>C	p.Leu2Pro	missense	Exon 2 of 6	NP_001269262.2	A0A590UJW4
TSEN34	NM_001282332.2		c.5T>C	p.Leu2Pro	missense	Exon 2 of 5	NP_001269261.1	Q9BSV6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSEN34	ENST00000396388.3	TSL:1 MANE Select	c.5T>C	p.Leu2Pro	missense	Exon 1 of 4	ENSP00000379671.2	Q9BSV6
TSEN34	ENST00000302937.8	TSL:1	c.5T>C	p.Leu2Pro	missense	Exon 2 of 5	ENSP00000305524.4	Q9BSV6
TSEN34	ENST00000396383.5	TSL:1	c.5T>C	p.Leu2Pro	missense	Exon 2 of 5	ENSP00000379667.1	Q9BSV6

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.0000600

AC:

AN:

150070

AF XY:

0.0000124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000323

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.0000215

AC:

AN:

1397848

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

689644

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31560

American (AMR)

AF:

0.000279

AC:

AN:

35808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25148

East Asian (EAS)

AF:

0.00

AC:

AN:

35862

South Asian (SAS)

AF:

0.00

AC:

AN:

79320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4072

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1079224

Other (OTH)

AF:

0.000121

AC:

AN:

57826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.000262

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67990

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000625

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.52

M_CAP

Pathogenic

0.82

MetaRNN

Uncertain

0.61

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.9

PhyloP100

0.82

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

1.0

REVEL

Uncertain

0.38

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.53

MutPred

0.54

Gain of catalytic residue at L2 (P = 0.0022)

MVP

0.79

MPC

1.3

ClinPred

0.39

GERP RS

4.1

PromoterAI

0.052

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.55

gMVP

0.92

Mutation Taster

=77/23

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over