Genetic Variant TSEN54:p.Glu4_Pro7dup (chr17-75516563-G-GGAGCCCGAGCCC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_207346.3(TSEN54):c.11_22dupAGCCCGAGCCCG(p.Glu4_Pro7dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000711 in 1,124,736 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

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

Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

TSEN54
NM_207346.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.417

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 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_207346.3.

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.11_22dupAGCCCGAGCCCG	p.Glu4_Pro7dup	disruptive_inframe_insertion	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.11_22dupAGCCCGAGCCCG	p.Glu4_Pro7dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000327487.6	Q7Z6J9-1
TSEN54	ENST00000680999.1		c.11_22dupAGCCCGAGCCCG	p.Glu4_Pro7dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000504984.1	A0A7P0Z413
TSEN54	ENST00000915433.1		c.11_22dupAGCCCGAGCCCG	p.Glu4_Pro7dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes

AF:

0.0000462

AC:

AN:

129752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000201

AC:

AN:

994984

Hom.:

Cov.:

AF XY:

0.00000427

AC XY:

AN XY:

468318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19752

American (AMR)

AF:

0.00

AC:

AN:

5514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10612

East Asian (EAS)

AF:

0.0000581

AC:

AN:

17218

South Asian (SAS)

AF:

0.00

AC:

AN:

18780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2448

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

866802

Other (OTH)

AF:

0.0000267

AC:

AN:

37464

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

AF:

0.0000462

AC:

AN:

129752

Hom.:

Cov.:

AF XY:

0.0000631

AC XY:

AN XY:

63346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

34638

American (AMR)

AF:

0.00

AC:

AN:

13204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2994

East Asian (EAS)

AF:

0.00116

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8494

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

58354

Other (OTH)

AF:

0.00

AC:

AN:

1778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.42

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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17-75516563-GGAGCCC-GGAGCCCGAGCCCGAGCCC

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