Genetic Variant TSEN54:p.Glu6Asp (chr17-75516578-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_207346.3(TSEN54):c.18G>C(p.Glu6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000995 in 1,004,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E6Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000010 ( 0 hom. )

Consequence

TSEN54
NM_207346.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.109

Publications

0 publications found

Variant links:

Genes affected

TSEN54 (HGNC:27561): (tRNA splicing endonuclease subunit 54) This gene encodes a subunit of the tRNA splicing endonuclease complex, which catalyzes the removal of introns from precursor tRNAs. The complex is also implicated in pre-mRNA 3-prime end processing. Mutations in this gene result in pontocerebellar hypoplasia type 2.[provided by RefSeq, Oct 2009]

TSEN54 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 2A
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
pontocerebellar hypoplasia type 4
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
pontocerebellar hypoplasia type 5
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
pontocerebellar hypoplasia type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TSEN54 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.12117544).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207346.3. 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
	TSEN54	NM_207346.3	MANE Select	c.18G>C	p.Glu6Asp	missense	Exon 1 of 11	NP_997229.2	Q7Z6J9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSEN54	ENST00000333213.11	TSL:1 MANE Select	c.18G>C	p.Glu6Asp	missense	Exon 1 of 11	ENSP00000327487.6	Q7Z6J9-1
TSEN54	ENST00000680999.1		c.18G>C	p.Glu6Asp	missense	Exon 1 of 11	ENSP00000504984.1	A0A7P0Z413
TSEN54	ENST00000915433.1		c.18G>C	p.Glu6Asp	missense	Exon 1 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.95e-7

AC:

AN:

1004984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

473204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20052

American (AMR)

AF:

0.00

AC:

AN:

5842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11032

East Asian (EAS)

AF:

0.00

AC:

AN:

18578

South Asian (SAS)

AF:

0.00

AC:

AN:

18886

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2498

European-Non Finnish (NFE)

AF:

0.00000115

AC:

AN:

872866

Other (OTH)

AF:

0.00

AC:

AN:

38116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.1

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.0071

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.34

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

-0.11

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.46

REVEL

Benign

0.038

Sift

Benign

0.057

Sift4G

Benign

0.52

Polyphen

0.0010

Vest4

0.10

MutPred

0.084

Loss of glycosylation at P5 (P = 0.0705)

MVP

0.49

MPC

0.23

ClinPred

0.10

GERP RS

1.1

PromoterAI

-0.0018

Neutral

(source)

Varity_R

0.041

gMVP

0.18

Mutation Taster

=95/5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over