rs11559205

chr17-75517596-A-Cchr17-75517596-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_207346.3(TSEN54):c.409A>C(p.Ile137Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0724 in 1,613,612 control chromosomes in the GnomAD database, including 5,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (975 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4093 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 17-75517596-A-C is Benign according to our data. Variant chr17-75517596-A-C is described in ClinVar as [Benign]. Clinvar id is 160134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75517596-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN54	NM_207346.3	c.409A>C	p.Ile137Leu	missense_variant	5/11	ENST00000333213.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN54	ENST00000333213.11	c.409A>C	p.Ile137Leu	missense_variant	5/11	1	NM_207346.3	P1

Frequencies

GnomAD3 genomes AF: 0.0969 AC: 14715 AN: 151824 Hom.: 970 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0753

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0816

Gnomad FIN AF: 0.0683

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0691

Gnomad OTH AF: 0.0938

GnomAD3 exomes AF: 0.0726 AC: 18249 AN: 251400 Hom.: 844 AF XY: 0.0727 AC XY: 9876 AN XY: 135878

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.0641

Gnomad ASJ exome AF: 0.0637

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0828

Gnomad FIN exome AF: 0.0754

Gnomad NFE exome AF: 0.0694

Gnomad OTH exome AF: 0.0717

GnomAD4 exome AF: 0.0699 AC: 102154 AN: 1461670 Hom.: 4093 Cov.: 33 AF XY: 0.0702 AC XY: 51078 AN XY: 727118

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.0669

Gnomad4 ASJ exome AF: 0.0616

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0842

Gnomad4 FIN exome AF: 0.0742

Gnomad4 NFE exome AF: 0.0673

Gnomad4 OTH exome AF: 0.0763

GnomAD4 genome AF: 0.0970 AC: 14738 AN: 151942 Hom.: 975 Cov.: 32 AF XY: 0.0959 AC XY: 7118 AN XY: 74250

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.0752

Gnomad4 ASJ AF: 0.0663

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.0823

Gnomad4 FIN AF: 0.0683

Gnomad4 NFE AF: 0.0691

Gnomad4 OTH AF: 0.0928

Alfa AF: 0.0691 Hom.: 527

Bravo AF: 0.102

TwinsUK AF: 0.0615 AC: 228

ALSPAC AF: 0.0672 AC: 259

ESP6500AA AF: 0.166 AC: 731

ESP6500EA AF: 0.0674 AC: 580

ExAC AF: 0.0748 AC: 9078

Asia WGS AF: 0.0430 AC: 151 AN: 3478

EpiCase AF: 0.0722

EpiControl AF: 0.0709

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Pontocerebellar hypoplasia type 2A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Benign. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with pontocerebellar hypoplasia type 2A (MIM#277470) and type 4 (MIM#225753). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to leucine. (I) 0251 - This variant is heterozygous. (I) 0307 - Variant is present in gnomAD (v2) at a frequency >=0.05 (19200 heterozygotes, 1035 homozygotes). (SB) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated endA superfamily domain (NCBI Conserved Domain). (I) 0805 - This variant has strong previous evidence of being benign in unrelated individuals. (ClinVar). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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. -

Pontocerebellar hypoplasia type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Pontocerebellar hypoplasia type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	26
Dann	Benign	0.94
Eigen	Benign	0.012
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.00022	P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.11
Sift	Benign	0.16	T;D
Sift4G	Benign	0.17	T;D
Polyphen		0.97	.;D
Vest4		0.18
MPC		0.37
ClinPred		0.035	T
GERP RS		5.1
Varity_R		0.48
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 6

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

Publications

LitVar

Other links and lift over

dbSNP: rs11559205; hg19: chr17-73513677; COSMIC: COSV58689943; COSMIC: COSV58689943;