rs146571352

Positions:

chr2-55647424-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_033109.5(PNPT1):c.1525G>A(p.Val509Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,608,332 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 12 hom. )

Consequence

PNPT1
NM_033109.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:3O:1

Conservation

PhyloP100: 7.36

Variant links:

Genes affected

PNPT1 (HGNC:23166): (polyribonucleotide nucleotidyltransferase 1) The protein encoded by this gene belongs to the evolutionary conserved polynucleotide phosphorylase family comprised of phosphate dependent 3'-to-5' exoribonucleases implicated in RNA processing and degradation. This enzyme is predominantly localized in the mitochondrial intermembrane space and is involved in import of RNA to mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency-13 and autosomal recessive nonsyndromic deafness-70. Related pseudogenes are found on chromosomes 3 and 7. [provided by RefSeq, Dec 2012]

PNPT1 links:

PNPT1 (HGNC:):

PNPT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a strand (size 10) in uniprot entity PNPT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_033109.5

BP4

Computational evidence support a benign effect (MetaRNN=0.16386932).

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPT1	NM_033109.5 linkuse as main transcript	c.1525G>A	p.Val509Ile	missense_variant	19/28	ENST00000447944.7	NP_149100.2	Q8TCS8
PNPT1	XM_005264629.3 linkuse as main transcript	c.1285G>A	p.Val429Ile	missense_variant	19/28		XP_005264686.1
PNPT1	XM_017005172.2 linkuse as main transcript	c.1285G>A	p.Val429Ile	missense_variant	18/27		XP_016860661.1
PNPT1	XM_047446161.1 linkuse as main transcript	c.*57G>A		3_prime_UTR_variant	20/20		XP_047302117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPT1	ENST00000447944.7 linkuse as main transcript	c.1525G>A	p.Val509Ile	missense_variant	19/28	1	NM_033109.5	ENSP00000400646.2		Q8TCS8

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00187

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000972

AC:

244

AN:

250944

Hom.:

AF XY:

0.000966

AC XY:

131

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000552

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000524

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00172

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.00204

AC:

2974

AN:

1456200

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1430

AN XY:

724414

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000650

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000434

Gnomad4 FIN exome

AF:

0.000151

Gnomad4 NFE exome

AF:

0.00245

Gnomad4 OTH exome

AF:

0.00280

GnomAD4 genome

AF:

0.00109

AC:

166

AN:

152132

Hom.:

Cov.:

AF XY:

0.000982

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000947

Gnomad4 NFE

AF:

0.00187

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00146

Hom.:

Bravo

AF:

0.00111

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000749

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 16, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 27, 2023	Variant summary: PNPT1 c.1525G>A (p.Val509Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 1608332 control chromosomes in the gnomAD database, including 12 homozygotes, strongly suggesting the variant is a benign polymorphism. c.1525G>A has been reported in the literature in an individual affected with mild and chronic encephalopathy and deafness (Pennisi_2022). However, this report does not provide unequivocal conclusions about association of the variant with PNPT1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33199448). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as uncertain significance and two classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PNPT1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2024	Observed with a second variant in PNPT1 in a patient with mitochondrial encephalopathy in published literature (PMID: 33199448); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26633545, 34498404, 33199448) -

Combined oxidative phosphorylation defect type 13

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Baylor Genetics

Feb 05, 2014

Likely pathogenicity based on finding it once in our laboratory in trans with another variant [T531R] in an 18-year-old male with profound intellectual disability, severe bilateral hearing loss, hypotonia, dysmorphisms, short stature, microcephaly, hyperextensibility, myopia, cataract, congenital heart disease, fused kidneys, small testicles, type II diabetes, immunodeficiency (healthy sib NOT compound heterozygous). Variant likely pathogenic in recessive state; heterozygotes would be carriers. -

Spinocerebellar ataxia type 25

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2021

The c.1525G>A (p.V509I) alteration is located in exon 19 (coding exon 19) of the PNPT1 gene. This alteration results from a G to A substitution at nucleotide position 1525, causing the valine (V) at amino acid position 509 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PNPT1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

The PNPT1 c.1525G>A variant is predicted to result in the amino acid substitution p.Val509Ile. This variant was reported in the compound heterozygous state in an individual with mitochondrial disease of variable severity. Specifically, the patient presented with respiratory anomalies, elevated bilirubin, encephalopathy, hypotonia, and cardiac anomalies (Table 1, Patient 1, Pennisi et al 2022. PubMed ID: 33199448). This variant is reported in 0.17% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 12 homozygotes in the gnomADv4.1.0 dataset (https://gnomad.broadinstitute.org/variant/2-55647424-C-T?dataset=gnomad_r4). While we suspect this variant is likely benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive nonsyndromic hearing loss 70;C4706283:Combined oxidative phosphorylation defect type 13

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as Uncertain significance and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.080

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.015

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.89

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.83

REVEL

Benign

0.24

Sift

Benign

0.14

Sift4G

Benign

0.34

Polyphen

0.99

Vest4

0.59

MVP

0.34

MPC

0.52

ClinPred

0.044

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.24

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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