rs1057519631

Variant names:

• chr2-24793221-G-A
• rs1057519631
• NM_001013663.2:c.157C>T
• PTRHD1 p.His53Tyr

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001013663.2(PTRHD1):​c.157C>T​(p.His53Tyr) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTRHD1 NM_001013663.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.74
• Publications: 5 publications found

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]

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]

LOC105369164 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 2-24793221-G-A is Pathogenic according to our data. Variant chr2-24793221-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 375735.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013663.2. 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
	PTRHD1	NM_001013663.2	MANE Select	c.157C>T	p.His53Tyr	missense	Exon 1 of 2	NP_001013685.1	Q6GMV3
	CENPO	NM_001322101.2	MANE Select	c.-349G>A		upstream_gene	N/A	NP_001309030.1	Q9BU64-1
	CENPO	NM_024322.4		c.-368G>A		upstream_gene	N/A	NP_077298.1	Q9BU64-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTRHD1	ENST00000328379.6	TSL:1 MANE Select	c.157C>T	p.His53Tyr	missense	Exon 1 of 2	ENSP00000330389.4	Q6GMV3
	PTRHD1	ENST00000915622.1		c.157C>T	p.His53Tyr	missense	Exon 1 of 2	ENSP00000585681.1
	CENPO	ENST00000868050.1		c.-349G>A		5_prime_UTR	Exon 1 of 8	ENSP00000538109.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		8.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
PromoterAI		0.076	Neutral
Varity_R		0.95
gMVP		0.90
Mutation Taster		=156/144	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057519631;

hg19: chr2-25016090;