rs150169668

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_207346.3(TSEN54):c.1328C>G(p.Ser443Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,614,170 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 15 hom., cov: 32)

Exomes 𝑓: 0.013 ( 197 hom. )

Consequence

TSEN54
NM_207346.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.90

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003773123).

BP6

Variant 17-75523677-C-G is Benign according to our data. Variant chr17-75523677-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 160128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0102 (1555/152296) while in subpopulation SAS AF= 0.0182 (88/4832). AF 95% confidence interval is 0.0151. There are 15 homozygotes in gnomad4. There are 797 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN54	NM_207346.3 linkuse as main transcript	c.1328C>G	p.Ser443Cys	missense_variant	10/11	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.1328C>G	p.Ser443Cys	missense_variant	10/11	1	NM_207346.3	ENSP00000327487	P1	Q7Z6J9-1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1558

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.00949

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.0245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0122

AC:

3065

AN:

251478

Hom.:

AF XY:

0.0133

AC XY:

1810

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00221

Gnomad AMR exome

AF:

0.00515

Gnomad ASJ exome

AF:

0.00774

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0231

Gnomad FIN exome

AF:

0.0258

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0134

AC:

19627

AN:

1461874

Hom.:

197

Cov.:

AF XY:

0.0136

AC XY:

9906

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00608

Gnomad4 ASJ exome

AF:

0.00788

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0231

Gnomad4 FIN exome

AF:

0.0236

Gnomad4 NFE exome

AF:

0.0135

Gnomad4 OTH exome

AF:

0.0130

GnomAD4 genome

AF:

0.0102

AC:

1555

AN:

152296

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

797

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00233

Gnomad4 AMR

AF:

0.00948

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0182

Gnomad4 FIN

AF:

0.0245

Gnomad4 NFE

AF:

0.0130

Gnomad4 OTH

AF:

0.0113

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.00836

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.0115

AC:

1394

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0135

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 23, 2015	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Pontoneocerebellar hypoplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Benign

0.81

DEOGEN2

Benign

0.077

Eigen

Benign

0.15

Eigen_PC

Benign

0.059

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0038

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.7

REVEL

Benign

0.17

Sift

Benign

0.047

Sift4G

Benign

0.10

Polyphen

0.97

Vest4

0.10

MPC

0.67

ClinPred

0.016

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.078

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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