rs563575998

chr17-75516562-T-TGGAGCC

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4 BP6 BA1

The NM_207346.3(TSEN54):c.3_8dup(p.Glu6_Pro7dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,141,802 control chromosomes in the GnomAD database, including 2,608 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.070 (424 hom., cov: 32)
  • Exomes 𝑓: 0.065 (2184 hom.)
• Consequence: TSEN54 NM_207346.3 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.10

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 -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_207346.3.
• BP6: Variant 17-75516562-T-TGGAGCC is Benign according to our data. Variant chr17-75516562-T-TGGAGCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96674.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=5, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN54	NM_207346.3	c.3_8dup	p.Glu6_Pro7dup	inframe_insertion	1/11	ENST00000333213.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN54	ENST00000333213.11	c.3_8dup	p.Glu6_Pro7dup	inframe_insertion	1/11	1	NM_207346.3	P1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10382 AN: 149324 Hom.: 423 Cov.: 32

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.0749

Gnomad AMR AF: 0.0635

Gnomad ASJ AF: 0.0645

Gnomad EAS AF: 0.000783

Gnomad SAS AF: 0.0826

Gnomad FIN AF: 0.0660

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0679

Gnomad OTH AF: 0.0697

GnomAD4 exome AF: 0.0647 AC: 64199 AN: 992370 Hom.: 2184 Cov.: 28 AF XY: 0.0644 AC XY: 30073 AN XY: 467008

Gnomad4 AFR exome AF: 0.0861

Gnomad4 AMR exome AF: 0.0613

Gnomad4 ASJ exome AF: 0.0536

Gnomad4 EAS exome AF: 0.000468

Gnomad4 SAS exome AF: 0.0784

Gnomad4 FIN exome AF: 0.0648

Gnomad4 NFE exome AF: 0.0651

Gnomad4 OTH exome AF: 0.0667

GnomAD4 genome AF: 0.0695 AC: 10389 AN: 149432 Hom.: 424 Cov.: 32 AF XY: 0.0690 AC XY: 5030 AN XY: 72914

Gnomad4 AFR AF: 0.0824

Gnomad4 AMR AF: 0.0635

Gnomad4 ASJ AF: 0.0645

Gnomad4 EAS AF: 0.000785

Gnomad4 SAS AF: 0.0835

Gnomad4 FIN AF: 0.0660

Gnomad4 NFE AF: 0.0679

Gnomad4 OTH AF: 0.0689

Alfa AF: 0.0688 Hom.: 13

Asia WGS AF: 0.0310 AC: 96 AN: 3158

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 08, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 08, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2019	- -

Pontoneocerebellar hypoplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pontocerebellar hypoplasia type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398124622; hg19: chr17-73512643;