17-75516561-A-G

Variant names:

• chr17-75516561-A-G
• rs587784478
• NM_207346.3:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000333213.11(TSEN54):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 959,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: TSEN54 ENST00000333213.11 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.235
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 11 pathogenic variants. Next in-frame start position is after 102 codons. Genomic position: 75517179. Lost 0.192 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000333213.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	NM_207346.3	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 11	NP_997229.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	ENST00000333213.11	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000327487.6
	TSEN54	ENST00000680999.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000504984.1
	TSEN54	ENST00000545228.3	TSL:5	c.1A>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000438169.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000417 AC: 4 AN: 959268 Hom.: 0 Cov.: 28 AF XY: 0.00000443 AC XY: 2 AN XY: 451502

African (AFR) AF: 0.00 AC: 0 AN: 18768

American (AMR) AF: 0.00 AC: 0 AN: 5158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10064

East Asian (EAS) AF: 0.00 AC: 0 AN: 16928

South Asian (SAS) AF: 0.00 AC: 0 AN: 18058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2302

European-Non Finnish (NFE) AF: 0.00000478 AC: 4 AN: 837024

Other (OTH) AF: 0.00 AC: 0 AN: 35802

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Benign	0.63
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.030	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.91	T
PhyloP100		0.23
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.036	D
Polyphen		0.79	P
Vest4		0.35
MutPred		0.98		Loss of glycosylation at P3 (P = 0.0843)
MVP		0.68
ClinPred		0.97	D
GERP RS		4.5
PromoterAI		0.35	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.94
gMVP		0.34

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: rs587784478; hg19: chr17-73512642;