17-75522247-A-T

Variant names:

• chr17-75522247-A-T
• rs77247739
• NM_207346.3:c.1166A>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.1166A>T​(p.Gln389Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q389H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.412
• Publications: 15 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=0.07053667).

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.1166A>T	p.Gln389Leu	missense	Exon 8 of 11	NP_997229.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	ENST00000333213.11	TSL:1 MANE Select	c.1166A>T	p.Gln389Leu	missense	Exon 8 of 11	ENSP00000327487.6
	TSEN54	ENST00000680999.1		c.1166A>T	p.Gln389Leu	missense	Exon 8 of 11	ENSP00000504984.1
	TSEN54	ENST00000915433.1		c.1166A>T	p.Gln389Leu	missense	Exon 8 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 322

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.7
DANN	Benign	0.65
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.41
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.065
Sift	Benign	0.32	T
Sift4G	Benign	0.68	T
Polyphen		0.0070	B
Vest4		0.092
MutPred		0.26		Gain of catalytic residue at Q389 (P = 0.0899)
MVP		0.47
MPC		0.25
ClinPred		0.054	T
GERP RS		-0.063
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.36

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: rs77247739; hg19: chr17-73518328;