Genetic Variant PTRHD1:p.Ala57ArgfsTer26 (chr2-24793181-GGGTGGTCGCGGTGAGTGTGCAAGGCCGC-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The NM_001013663.2(PTRHD1):c.169_196delGCGGCCTTGCACACTCACCGCGACCACC(p.Ala57ArgfsTer26) variant causes a frameshift change. The variant allele was found at a frequency of 0.000162 in 1,613,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

PTRHD1
NM_001013663.2 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.04

Variant links:

Genes affected

PTRHD1 (HGNC:33782): (peptidyl-tRNA hydrolase domain containing 1) This gene encodes the enzyme peptidyl-tRNA hydrolase. Peptidyl-tRNA hydrolases perform the essential function of recycling peptidyl-tRNAs. Mutations in this gene are associated with autosomal-recessive intellectual disability and parkinsonism. [provided by RefSeq, May 2017]

PTRHD1 links:

CENPO (HGNC:28152): (centromere protein O) This gene encodes a component of the interphase centromere complex. The encoded protein is localized to the centromere throughout the cell cycle and is required for bipolar spindle assembly, chromosome segregation and checkpoint signaling during mitosis. Alternatively spliced transcript variants encoding multiple protein isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

CENPO links:

LOC105369164 (HGNC:):

LOC105369164 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP5

Variant 2-24793181-GGGTGGTCGCGGTGAGTGTGCAAGGCCGC-G is Pathogenic according to our data. Variant chr2-24793181-GGGTGGTCGCGGTGAGTGTGCAAGGCCGC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3061964.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTRHD1	NM_001013663.2 link	c.169_196delGCGGCCTTGCACACTCACCGCGACCACC	p.Ala57ArgfsTer26	frameshift_variant	Exon 1 of 2	ENST00000328379.6	NP_001013685.1
CENPO	NM_001322101.2 link	c.-388_-361delGGTGGTCGCGGTGAGTGTGCAAGGCCGC		upstream_gene_variant		ENST00000380834.7	NP_001309030.1	Q9BU64-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTRHD1	ENST00000328379.6 link	c.169_196delGCGGCCTTGCACACTCACCGCGACCACC	p.Ala57ArgfsTer26	frameshift_variant	Exon 1 of 2	1	NM_001013663.2	ENSP00000330389.4		Q6GMV3
CENPO	ENST00000380834.7 link	c.-388_-361delGGTGGTCGCGGTGAGTGTGCAAGGCCGC		upstream_gene_variant		5	NM_001322101.2	ENSP00000370214.2		Q9BU64-1

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000136

AC:

AN:

250020

AF XY:

0.0000812

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1461082

Hom.:

AF XY:

0.000117

AC XY:

AN XY:

726882

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

AC:

AN:

33476

Gnomad4 AMR exome

AF:

0.0000671

AC:

AN:

44700

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26102

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39694

Gnomad4 SAS exome

AF:

0.0000116

AC:

AN:

86238

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

52836

Gnomad4 NFE exome

AF:

0.0000989

AC:

110

AN:

1111894

Gnomad4 Remaining exome

AF:

0.0000663

AC:

AN:

60376

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000492

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00159

AC:

0.0015873

AN:

0.0015873

Gnomad4 AMR

AF:

0.000196

AC:

0.000196053

AN:

0.000196053

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000193

AC:

0.00019305

AN:

0.00019305

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000735

AC:

0.000073497

AN:

0.000073497

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000349

Hom.:

Bravo

AF:

0.000518

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities

Pathogenic:1

Mar 13, 2024

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jul 15, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 84 amino acids are replaced with 25 different amino acids; This variant is associated with the following publications: (PMID: 36344539, 30398675, 34765690) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=14/186

disease causing (long InDel)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over