rs730882234

Variant names:

• chr17-59697725-T-G
• rs730882234
• NM_016077.5:c.254A>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.86
• Publications: 6 publications found

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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016077.5. 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
	PTRH2	NM_016077.5	MANE Select	c.254A>C	p.Gln85Pro	missense	Exon 2 of 2	NP_057161.1	Q9Y3E5
	PTRH2	NM_001015509.3		c.257A>C	p.Gln86Pro	missense	Exon 3 of 3	NP_001015509.1	J3KQ48

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTRH2	ENST00000393038.3	TSL:1 MANE Select	c.254A>C	p.Gln85Pro	missense	Exon 2 of 2	ENSP00000376758.2	Q9Y3E5
	PTRH2	ENST00000409433.2	TSL:1	c.257A>C	p.Gln86Pro	missense	Exon 3 of 3	ENSP00000387180.2	J3KQ48
	PTRH2	ENST00000470557.2	TSL:6	c.254A>C	p.Gln85Pro	missense	Exon 1 of 1	ENSP00000464327.1	Q9Y3E5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset (3)
3	-	-	Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1 (3)
1	-	-	Cerebellar ataxia;C0557874:Global developmental delay;C1384666:Hearing impairment (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Loss of MoRF binding (P = 0.0357)
MVP		0.81
MPC		0.45
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.96
Mutation Taster		=0/100	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: rs730882234; hg19: chr17-57775086;