rs146571352

chr2-55647424-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:3 O:1
• Conservation: PhyloP100: 7.36

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_033109.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.16386932).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPT1	ENST00000447944.7	c.1525G>A	p.Val509Ile	missense_variant	19/28	1	NM_033109.5	P1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152016 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.000966 AC XY: 131 AN XY: 135658

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.: 12 Cov.: 30 AF XY: 0.00197 AC XY: 1430 AN XY: 724414

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.: 0 Cov.: 32 AF XY: 0.000982 AC XY: 73 AN XY: 74350

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.: 0

Bravo AF: 0.00111

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 16, 2015	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	PNPT1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2023	Observed in a patient with mitochondrial encephalopathy in published literature (Pennisi et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26633545, 33199448, 34498404) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

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. -

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. -

Spinocerebellar ataxia type 25 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

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	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.080	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.89	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.24
Sift	Benign	0.14	T
Sift4G	Benign	0.34	T
Polyphen		0.99	D
Vest4		0.59
MVP		0.34
MPC		0.52
ClinPred		0.044	T
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

Other links and lift over

dbSNP: rs146571352; hg19: chr2-55874559; COSMIC: COSV99037457; COSMIC: COSV99037457;