17-75516576-G-T

Variant names:

• chr17-75516576-G-T
• rs1377971286
• NM_207346.3:c.16G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_207346.3(TSEN54):​c.16G>T​(p.Glu6*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,004,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: TSEN54 NM_207346.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.115
• Publications: 0 publications found

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]

TSEN54 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pontocerebellar hypoplasia type 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 72 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-75516576-G-T is Pathogenic according to our data. Variant chr17-75516576-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2701058.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207346.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	NM_207346.3	MANE Select	c.16G>T	p.Glu6*	stop_gained	Exon 1 of 11	NP_997229.2	Q7Z6J9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	ENST00000333213.11	TSL:1 MANE Select	c.16G>T	p.Glu6*	stop_gained	Exon 1 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.16G>T	p.Glu6*	stop_gained	Exon 1 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.16G>T	p.Glu6*	stop_gained	Exon 1 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000299 AC: 3 AN: 1004008 Hom.: 0 Cov.: 38 AF XY: 0.00000423 AC XY: 2 AN XY: 472674

African (AFR) AF: 0.00 AC: 0 AN: 20018

American (AMR) AF: 0.00 AC: 0 AN: 5808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10986

East Asian (EAS) AF: 0.00 AC: 0 AN: 18464

South Asian (SAS) AF: 0.00 AC: 0 AN: 18874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2496

European-Non Finnish (NFE) AF: 0.00000344 AC: 3 AN: 872252

Other (OTH) AF: 0.00 AC: 0 AN: 38054

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	36
DANN	Uncertain	0.98
Eigen	Benign	0.081
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.021	N
PhyloP100		0.12
Vest4		0.087
GERP RS		2.3
PromoterAI		-0.0074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1377971286; hg19: chr17-73512657;