rs730882234

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_016077.5(PTRH2):c.254A>C(p.Gln85Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

PTRH2
NM_016077.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.86

Publications

6 publications found

Variant links:

Genes affected

PTRH2 (HGNC:24265): (peptidyl-tRNA hydrolase 2) The protein encoded by this gene is a mitochondrial protein with two putative domains, an N-terminal mitochondrial localization sequence, and a UPF0099 domain. In vitro assays suggest that this protein possesses peptidyl-tRNA hydrolase activity, to release the peptidyl moiety from tRNA, thereby preventing the accumulation of dissociated peptidyl-tRNA that could reduce the efficiency of translation. This protein also plays a role regulating cell survival and death. It promotes survival as part of an integrin-signaling pathway for cells attached to the extracellular matrix (ECM), but also promotes apoptosis in cells that have lost their attachment to the ECM, a process called anoikos. After loss of cell attachment to the ECM, this protein is phosphorylated, is released from the mitochondria into the cytosol, and promotes caspase-independent apoptosis through interactions with transcriptional regulators. This gene has been implicated in the development and progression of tumors, and mutations in this gene have been associated with an infantile multisystem neurologic, endocrine, and pancreatic disease (INMEPD) characterized by intellectual disability, postnatal microcephaly, progressive cerebellar atrophy, hearing impairment, polyneuropathy, failure to thrive, and organ fibrosis with exocrine pancreas insufficiency (PMID: 25574476). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

PTRH2 Gene-Disease associations (from GenCC):

neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
infantile multisystem neurologic-endocrine-pancreatic disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PTRH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 17-59697725-T-G is Pathogenic according to our data. Variant chr17-59697725-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 183332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PTRH2	NM_016077.5 link	c.254A>C	p.Gln85Pro	missense_variant	Exon 2 of 2	ENST00000393038.3	NP_057161.1
PTRH2	NM_001015509.3 link	c.257A>C	p.Gln86Pro	missense_variant	Exon 3 of 3		NP_001015509.1
PTRH2	XM_011524887.3 link	c.254A>C	p.Gln85Pro	missense_variant	Exon 2 of 2		XP_011523189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PTRH2	ENST00000393038.3 link	c.254A>C	p.Gln85Pro	missense_variant	Exon 2 of 2	1	NM_016077.5	ENSP00000376758.2
PTRH2	ENST00000409433.2 link	c.257A>C	p.Gln86Pro	missense_variant	Exon 3 of 3	1		ENSP00000387180.2
PTRH2	ENST00000470557.2 link	c.254A>C	p.Gln85Pro	missense_variant	Exon 1 of 1	6		ENSP00000464327.1
PTRH2	ENST00000587935.1 link	n.45+9646A>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset

Pathogenic:3

Jun 03, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jun 04, 2016

Hereditary Research Laboratory, Bethlehem University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

bilat severe w/mild MR and motor delay -

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1

Pathogenic:3

Nov 19, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 13, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Cerebellar ataxia;C0557874:Global developmental delay;C1384666:Hearing impairment

Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

D;.;D

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

4.3

H;.;H

PhyloP100

7.9

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.7

D;D;.

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.97

MutPred

0.94

Loss of MoRF binding (P = 0.0357);.;Loss of MoRF binding (P = 0.0357);

MVP

0.81

MPC

0.45

ClinPred

1.0

GERP RS

4.7

Varity_R

0.98

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over