2-24793251-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001013663.2(PTRHD1):c.127C>A(p.Pro43Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0011 in 1,613,936 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (44 hom.)
• Consequence: PTRHD1 NM_001013663.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.91

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009550095).
• BP6: Variant 2-24793251-G-T is Benign according to our data. Variant chr2-24793251-G-T is described in ClinVar as [Benign]. Clinvar id is 3043675.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-24793251-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00116 (1689/1461548) while in subpopulation SAS AF= 0.0186 (1605/86258). AF 95% confidence interval is 0.0178. There are 44 homozygotes in gnomad4_exome. There are 1171 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTRHD1	NM_001013663.2	c.127C>A	p.Pro43Thr	missense_variant	1/2	ENST00000328379.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTRHD1	ENST00000328379.6	c.127C>A	p.Pro43Thr	missense_variant	1/2	1	NM_001013663.2	P1
CENPO	ENST00000473706.5	c.-223G>T		5_prime_UTR_variant	1/7	2
CENPO	ENST00000473476.5	n.30-55G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152270 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00213 AC: 536 AN: 251056 Hom.: 10 AF XY: 0.00286 AC XY: 388 AN XY: 135846

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0171

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00116 AC: 1689 AN: 1461548 Hom.: 44 Cov.: 31 AF XY: 0.00161 AC XY: 1171 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152388 Hom.: 2 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74514

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000503 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.00214 AC: 260

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PTRHD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.32
Sift	Benign	0.033	D
Sift4G	Benign	0.061	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.57		Loss of loop (P = 0.0031);
MVP		0.43
MPC		0.57
ClinPred		0.12	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.55
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs545737721; hg19: chr2-25016120; COSMIC: COSV53232493; COSMIC: COSV53232493;