chr17-75522000-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The NM_207346.3(TSEN54):c.919G>T(p.Ala307Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,595,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 0 hom. )

Consequence

TSEN54
NM_207346.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:43O:2

Conservation

PhyloP100: 9.12

Publications

51 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 5
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
pontocerebellar hypoplasia type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
pontocerebellar hypoplasia type 4
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TSEN54 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-75522000-G-T is Pathogenic according to our data. Variant chr17-75522000-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.919G>T	p.Ala307Ser	missense	Exon 8 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.919G>T	p.Ala307Ser	missense	Exon 8 of 11	ENSP00000327487.6	Q7Z6J9-1
TSEN54	ENST00000680999.1		c.919G>T	p.Ala307Ser	missense	Exon 8 of 11	ENSP00000504984.1	A0A7P0Z413
TSEN54	ENST00000915433.1		c.919G>T	p.Ala307Ser	missense	Exon 8 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes

AF:

0.000894

AC:

136

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000903

AC:

189

AN:

209398

AF XY:

0.000954

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.000129

Gnomad ASJ exome

AF:

0.000543

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000547

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.000943

GnomAD4 exome

AF:

0.00135

AC:

1950

AN:

1443158

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

938

AN XY:

716560

show subpopulations

African (AFR)

AF:

0.000304

AC:

AN:

32922

American (AMR)

AF:

0.000190

AC:

AN:

42186

Ashkenazi Jewish (ASJ)

AF:

0.000310

AC:

AN:

25794

East Asian (EAS)

AF:

0.00

AC:

AN:

38298

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84088

European-Finnish (FIN)

AF:

0.000778

AC:

AN:

50140

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00166

AC:

1835

AN:

1104370

Other (OTH)

AF:

0.000805

AC:

AN:

59610

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

139

278

418

557

696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

168

224

280

<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:

0.000893

AC:

136

AN:

152230

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41540

American (AMR)

AF:

0.000392

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00172

AC:

117

AN:

67992

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00161

Hom.:

Bravo

AF:

0.000910

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000818

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (11)

Pontocerebellar hypoplasia type 2A (9)

Pontocerebellar hypoplasia type 4 (5)

Pontocerebellar hypoplasia type 2A;C1856974:Pontocerebellar hypoplasia type 4;C1857762:Pontocerebellar hypoplasia type 5 (3)

Pontoneocerebellar hypoplasia (3)

Pontocerebellar hypoplasia type 5 (2)

Amblyopia;C0026826:Hypertonia;C0557874:Global developmental delay (1)

Congenital cerebellar hypoplasia (1)

Global developmental delay;C4551563:Microcephaly (1)

Huppke-Brendel syndrome (1)

Inborn genetic diseases (1)

Intellectual disability (1)

Methylmalonic aciduria and homocystinuria type cblD;C1856974:Pontocerebellar hypoplasia type 4;C1857762:Pontocerebellar hypoplasia type 5 (1)

Olivopontocerebellar hypoplasia (1)

Pontocerebellar hypoplasia type 2A;C1856974:Pontocerebellar hypoplasia type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.027

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.75

M_CAP

Benign

0.069

MetaRNN

Benign

0.044

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.2

PhyloP100

9.1

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.76

REVEL

Uncertain

0.34

Sift

Uncertain

0.024

Sift4G

Uncertain

0.039

Polyphen

1.0

Vest4

0.41

MVP

0.82

MPC

0.58

ClinPred

0.48

GERP RS

5.1

Varity_R

0.15

gMVP

0.44

Mutation Taster

=36/64

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.52

Position offset: 7

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

Publications

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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