rs587784478

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-75516561-A-C
• chr17-75516561-A-G

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.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000069 in 144,942 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: 𝑓 0.0000069 (0 hom., cov: 33)
• Consequence: TSEN54 NM_207346.3 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.235
• Publications: 1 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 12 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
• PP5: Variant 17-75516561-A-C is Pathogenic according to our data. Variant chr17-75516561-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 160132.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	NM_207346.3	MANE Select	c.1A>C	p.Met1?	initiator_codon	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>C	p.Met1?	initiator_codon	Exon 1 of 11	ENSP00000327487.6
	TSEN54	ENST00000680999.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 11	ENSP00000504984.1
	TSEN54	ENST00000545228.3	TSL:5	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 11	ENSP00000438169.3

Frequencies

GnomAD3 genomes AF: 0.00000690 AC: 1 AN: 144942 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000682

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000690 AC: 1 AN: 144942 Hom.: 0 Cov.: 33 AF XY: 0.0000142 AC XY: 1 AN XY: 70658

African (AFR) AF: 0.00 AC: 0 AN: 39436

American (AMR) AF: 0.0000682 AC: 1 AN: 14656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3346

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65274

Other (OTH) AF: 0.00 AC: 0 AN: 1992

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Olivopontocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Benign	0.63
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.026	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.92	T
PhyloP100		0.23
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.41	T
Polyphen		0.62	P
Vest4		0.32
MutPred		0.99		Loss of glycosylation at P3 (P = 0.2002)
MVP		0.74
ClinPred		0.93	D
GERP RS		4.5
PromoterAI		0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.95
gMVP		0.25
Mutation Taster		=31/169	disease causing (ClinVar)

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;