17-75522250-TGCAGAGGAGCCAGC-T

Position:

• chr17-75522250-TGCAGAGGAGCCAGC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_207346.3(TSEN54):​c.1172_1185del​(p.Gln391ProfsTer39) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V390V) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSEN54 NM_207346.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.01

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-75522250-TGCAGAGGAGCCAGC-T is Pathogenic according to our data. Variant chr17-75522250-TGCAGAGGAGCCAGC-T is described in ClinVar as [Pathogenic]. Clinvar id is 30751.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN54	NM_207346.3	c.1172_1185del	p.Gln391ProfsTer39	frameshift_variant	8/11	ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11	c.1172_1185del	p.Gln391ProfsTer39	frameshift_variant	8/11	1	NM_207346.3	ENSP00000327487	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 07, 2023

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 30751). This variant is also known as c.1170_1183del. This premature translational stop signal has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 20956791). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln391Profs*39) in the TSEN54 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSEN54 are known to be pathogenic (PMID: 18711368, 20952379). -

Pontocerebellar hypoplasia type 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 19, 2010

- -

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: rs886037629; hg19: chr17-73518331;