rs113994152

Positions:

chr17-75522000-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000333213.11(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
ENST00000333213.11 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:39O:2

Conservation

PhyloP100: 9.12

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-75522000-G-T is Pathogenic according to our data. Variant chr17-75522000-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75522000-G-T is described in Lovd as [Pathogenic]. Variant chr17-75522000-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN54	NM_207346.3 linkuse as main transcript	c.919G>T	p.Ala307Ser	missense_variant	8/11	ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11 linkuse as main transcript	c.919G>T	p.Ala307Ser	missense_variant	8/11	1	NM_207346.3	ENSP00000327487	P1	Q7Z6J9-1

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

GnomAD3 exomes

AF:

0.000903

AC:

189

AN:

209398

Hom.:

AF XY:

0.000954

AC XY:

109

AN XY:

114276

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 SAS 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

Gnomad4 AFR exome

AF:

0.000304

Gnomad4 AMR exome

AF:

0.000190

Gnomad4 ASJ exome

AF:

0.000310

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.000778

Gnomad4 NFE exome

AF:

0.00166

Gnomad4 OTH exome

AF:

0.000805

GnomAD4 genome

AF:

0.000893

AC:

136

AN:

152230

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00172

Gnomad4 OTH

AF:

0.000946

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

Significance: Pathogenic

Submissions summary: Pathogenic:39Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the TSEN54 protein (p.Ala307Ser). This variant is present in population databases (rs113994152, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 18711368, 24886362, 26701950, 27430971). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2120). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSEN54 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30525188, 32360255, 24886362, 23177318, 26701950, 20952379, 18711368, 23307886, 27430971, 29410950, 29286531, 30792901, 31623504, 32404165, 30609409, 34426522, 31589614, 32629522, 31319225) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TSEN54: PM3:Very Strong, PM2, PP1 -

Pontocerebellar hypoplasia type 2A

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 05, 2024	Criteria applied: PM3_VSTR,PP1_STR,PM2_SUP,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.088%). The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002120). The variant has been observed in multiple (>3) similarly affected unrelated individuals, and reported to be homozygous in at least two similarly affected unrelated individuals (PMID: 24886362 , 26701950 , 27430971 , 29410950). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 18711368 , 20803644 , 29410950). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Feb 16, 2024	ACMG Criteria: PS3, PS4, PM3, PP1, PP5, Variant was found in heterozygous state -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 23, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2011	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Ala307Ser variant in TSEN54 was identified by our study in two siblings with pontocerebellar hypoplasia. This variant has been identified in 0.09241% (216/233752) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs113994152). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservational analyses do not provide strong support for or against an impact to the protein. The p.Ala307Ser variant in TSEN54 has been reported in 88 homozygous or heterozygous individuals with pontocerebellar hypoplasia, segregated with disease in 20 affected relatives from 10 families, and is believed to be a founder variant from the Netherlands (PMID: 23307886, 21368912, 29410950, 20803644, 27570394, 18711368, 24886362). The presence of this variant in combination with loss of function and missense variants (reported pathogenic in the literature) and in 8 individuals with pontocerebellar hypoplasia, included in the 88 individuals mentioned earlier, increases the likelihood that the p.Ala307Ser variant is pathogenic. This variant has also been reported pathogenic by multiple submitters in ClinVar (Variation ID: 2120). In summary, the p.Ala307Ser variant is pathogenic based off of our findings and multiple reports in ClinVar. ACMG/AMP Criteria applied: PM2, PM3_Strong, PP1_Strong (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 30, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Pontocerebellar hypoplasia type 4

Pathogenic:5

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 20, 2022	ACMG codes: PS4, PM2, PM3, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 19, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2011	- -

Pontoneocerebellar hypoplasia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2017	The p.Ala307Ser (NM_207346.2 c.919G>T) variant in TSEN54 has been reported in gr eater than 30 homozygous or compound heterozygous individuals with pontocerebell ar hypoplasia and segregated in several affected family members (Budde 2008, Cas sandrini 2010, Graham 2010, Simonati 2011, Valayannopoulos 2012, Zafeiriou 2013, Sanchez-Albisua 2014, Battini 2014, Maras-Genc 2015, and Samanta 2016). This va riant has been identified in 69/33,364 of European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs113994152). Al though this variant has been seen in the general population, its frequency is lo w enough to be consistent with a recessive carrier frequency. In summary, this v ariant meets criteria to be classified as pathogenic for pontocerebellar hypopla sia in an autosomal recessive manner based upon its biallelic occurrence in pati ents and segregation in affected family members. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 08, 2019	Variant summary: TSEN54 c.919G>T (p.Ala307Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0009 in 209398 control chromosomes (gnomAD). c.919G>T has been reported in the literature in multiple individuals affected with Pontocerebellar hypoplasia (e.g. Namavar_2011). These data indicate that the variant is very likely to be associated with disease. GeneReviews indicates the variant to be a common disease variant. Eight ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 19, 2018	The TSEN54 c.919G>T (p.Ala307Ser) variant is well-described in the literature as the most common pathogenic variant in individuals with varied subtypes of pontocerebellar hypoplasia (PCH). The p.Ala307Ser variant is reported in three studies and was found in a total of 57 patients, including 45 patients in a homozygous state, three in a compound heterozygous state and nine in a heterozygous state (Budde et al. 2008; Cassandrini et al. 2010; Namavar et al. 2011). Segregation of the variant with the disease in a recessive manner was shown in a large family (Budde et al. 2008). The p.Ala307Ser variant was absent from 724/730 controls, and is reported at a frequency of 0.00173 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Ala307Ser variant is classified as pathogenic for pontocerebellar hypoplasia. -

Pontocerebellar hypoplasia type 2A;C1856974:Pontocerebellar hypoplasia type 4;C1857762:Pontocerebellar hypoplasia type 5

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 18, 2024	PM3_Very Strong, PP1_Strong -

Pontocerebellar hypoplasia type 5

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. This variant was detected in homozygous state. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2011	- -

TSEN54 Pontocerebellar Hypoplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant has been reported in over 100 affected individuals as a homozygous or compound heterozygous change in patients with pontocerebellar hypoplasia and has been identified in 90% of individuals with pontocerebellar hypoplasia type 2 (PCH2, PMID: 24886362, 20301773). This variant has been shown to segregate with disease in more than 20 affected relatives from 10 families (PMID: 23307886, 21368912, 29410950, 20803644, 20956791, 23177318, 21468723, 21609947, 26701950, 27570394, 18711368, 24886362). Additionally, the c.919G>T (p.Ala307Ser) variant is a common homozygous missense variant that has been identified in 33 individuals, from nonconsanguineous families, who all survived until 11 years of age (PMID: 24886362). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.089% (213/240704) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.919G>T (p.Ala307Ser) variant on protein function. Based on the available evidence, the c.919G>T (p.Ala307Ser) variant is classified as Pathogenic. -

Pontocerebellar hypoplasia type 2A;C1856974:Pontocerebellar hypoplasia type 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

This variant has been previously reported as disease-causing and was found six times in our laboratory, either homozygous or compound heterozygous, in individuals with pontocerebellar hypoplasia. Heterozygotes would be expected to be asymptomatic carriers. -

Global developmental delay;C4551563:Microcephaly

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 10, 2015

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2021

The c.919G>T (p.A307S) alteration is located in coding exon 8 of the TSEN54 gene. This alteration results from a G to T substitution at nucleotide position 919, causing the alanine (A) at amino acid position 307 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.088% (213/240704) total alleles studied. The highest observed frequency was 0.173% (183/105724) of European (non-Finnish) alleles. This mutation is the most common variant causing TSEN54-related pontocerebellar hypoplasia, found in more than 90% of patients (Budde, 2008; Cassandrini, 2010; Namavar, 2011). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Amblyopia;C0026826:Hypertonia;C0557874:Global developmental delay

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

TSEN54-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 24, 2024

The TSEN54 c.919G>T variant is predicted to result in the amino acid substitution p.Ala307Ser. This variant is the most common cause of autosomal recessive pontocerebellar hypoplasia type 2A (Sánchez-Albisua et al. 2014. PubMed ID: 24886362; Budde et al. 2008. PubMed ID: 18711368). This variant is interpreted as pathogenic. -

Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 03, 2020

The variant c.919G>T, p.(Ala307Ser) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was M + P.The variant likely explains the NDD in this individual. -

Olivopontocerebellar hypoplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 25, 2014

- -

Congenital cerebellar hypoplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 06, 2014

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Sep 04, 2019

This variant was observed in compound heterozygosity with variant c.953del -

Pontocerebellar hypoplasia type 4;C2932714:Pontocerebellar hypoplasia type 2

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported, most recently, on 08-21-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

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

MutationTaster

Benign

0.99

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over