17-75516573-C-T

Variant names:

• chr17-75516573-C-T
• rs886053394
• NM_207346.3:c.13C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207346.3(TSEN54):​c.13C>T​(p.Pro5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,002,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P5P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.622
• 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 2A

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• pontocerebellar hypoplasia type 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07889184).

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.13C>T	p.Pro5Ser	missense	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.13C>T	p.Pro5Ser	missense	Exon 1 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.13C>T	p.Pro5Ser	missense	Exon 1 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.13C>T	p.Pro5Ser	missense	Exon 1 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000299 AC: 3 AN: 1002284 Hom.: 0 Cov.: 38 AF XY: 0.00000636 AC XY: 3 AN XY: 471898

African (AFR) AF: 0.00 AC: 0 AN: 19962

American (AMR) AF: 0.000174 AC: 1 AN: 5756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10930

East Asian (EAS) AF: 0.00 AC: 0 AN: 18198

South Asian (SAS) AF: 0.000106 AC: 2 AN: 18854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2486

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 871330

Other (OTH) AF: 0.00 AC: 0 AN: 37890

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.4
DANN	Benign	0.88
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.62
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.028
Sift	Benign	0.26	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.041
MutPred		0.12		Gain of phosphorylation at P5 (P = 0.0069)
MVP		0.28
MPC		0.26
ClinPred		0.067	T
GERP RS		-0.88
PromoterAI		0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.029
gMVP		0.29
Mutation Taster		=96/4	polymorphism

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: rs886053394; hg19: chr17-73512654;