rs138719855

Positions:

• chr17-75521696-G-A

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.624-9G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,612,748 control chromosomes in the GnomAD database, including 453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (14 hom., cov: 32)
  • Exomes 𝑓: 0.022 (439 hom.)
• Consequence: TSEN54 NM_207346.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006446
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.10

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 (BayesDel_noAF=-0.68).
• BP6: Variant 17-75521696-G-A is Benign according to our data. Variant chr17-75521696-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 160138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75521696-G-A is described in Lovd as [Likely_benign]. Variant chr17-75521696-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0145 (2208/152136) while in subpopulation NFE AF= 0.0242 (1644/67984). AF 95% confidence interval is 0.0232. There are 14 homozygotes in gnomad4. There are 975 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN54	NM_207346.3	c.624-9G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11	c.624-9G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_207346.3	ENSP00000327487	P1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2208 AN: 152018 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00768

Gnomad FIN AF: 0.00604

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0242

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0134 AC: 3337 AN: 248392 Hom.: 29 AF XY: 0.0137 AC XY: 1849 AN XY: 134634

Gnomad AFR exome AF: 0.00404

Gnomad AMR exome AF: 0.00770

Gnomad ASJ exome AF: 0.00589

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00833

Gnomad FIN exome AF: 0.00615

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0220 AC: 32114 AN: 1460612 Hom.: 439 Cov.: 30 AF XY: 0.0215 AC XY: 15647 AN XY: 726588

Gnomad4 AFR exome AF: 0.00466

Gnomad4 AMR exome AF: 0.00812

Gnomad4 ASJ exome AF: 0.00509

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00965

Gnomad4 FIN exome AF: 0.00662

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0145 AC: 2208 AN: 152136 Hom.: 14 Cov.: 32 AF XY: 0.0131 AC XY: 975 AN XY: 74368

Gnomad4 AFR AF: 0.00424

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00789

Gnomad4 FIN AF: 0.00604

Gnomad4 NFE AF: 0.0242

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.0189 Hom.: 23

Bravo AF: 0.0153

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0214

EpiControl AF: 0.0199

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Pontoneocerebellar hypoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.8
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.0		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: rs138719855; hg19: chr17-73517777;