rs150169668

chr17-75523677-C-Gchr17-75523677-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.90

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 -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 GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN54	NM_207346.3	c.1328C>G	p.Ser443Cys	missense_variant	10/11	ENST00000333213.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN54	ENST00000333213.11	c.1328C>G	p.Ser443Cys	missense_variant	10/11	1	NM_207346.3	P1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1558 AN: 152178 Hom.: 15 Cov.: 32

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.: 36 AF XY: 0.0133 AC XY: 1810 AN XY: 135918

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.: 35 AF XY: 0.0136 AC XY: 9906 AN XY: 727238

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.: 15 Cov.: 32 AF XY: 0.0107 AC XY: 797 AN XY: 74464

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.: 3

Bravo AF: 0.00836

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0109 AC: 94

ExAC AF: 0.0115 AC: 1394

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0135

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	24
Dann	Benign	0.81
DEOGEN2	Benign	0.077	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.059
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.17
Sift	Benign	0.047	D
Sift4G	Benign	0.10	T
Polyphen		0.97	D
Vest4		0.10
MPC		0.67
ClinPred		0.016	T
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

Other links and lift over

dbSNP: rs150169668; hg19: chr17-73519758; COSMIC: COSV104383166; COSMIC: COSV104383166;