rs374698153

Positions:

chr2-55647357-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_033109.5(PNPT1):c.1592C>G(p.Thr531Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,604,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

PNPT1
NM_033109.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 7.40

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

PP5

Variant 2-55647357-G-C is Pathogenic according to our data. Variant chr2-55647357-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 209184.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3, Pathogenic=1}. Variant chr2-55647357-G-C is described in Lovd as [Likely_pathogenic]. Variant chr2-55647357-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PNPT1	NM_033109.5 linkuse as main transcript	c.1592C>G	p.Thr531Arg	missense_variant	19/28	ENST00000447944.7	NP_149100.2
PNPT1	XM_005264629.3 linkuse as main transcript	c.1352C>G	p.Thr451Arg	missense_variant	19/28		XP_005264686.1
PNPT1	XM_017005172.2 linkuse as main transcript	c.1352C>G	p.Thr451Arg	missense_variant	18/27		XP_016860661.1
PNPT1	XM_047446161.1 linkuse as main transcript	c.*124C>G		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.1592C>G	p.Thr531Arg	missense_variant	19/28	1	NM_033109.5	ENSP00000400646	P1

Frequencies

GnomAD3 genomes

AF:

0.0000791

AC:

AN:

151782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249564

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134968

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000984

AC:

143

AN:

1452974

Hom.:

Cov.:

AF XY:

0.0000927

AC XY:

AN XY:

722620

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000134

GnomAD4 genome

AF:

0.0000791

AC:

AN:

151782

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74124

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000675

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 20, 2023	This variant is present in population databases (rs374698153, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 531 of the PNPT1 protein (p.Thr531Arg). This missense change has been observed in individuals with combined oxidative phosphorylation deficiency (PMID: 31752325, 33199448; external communication). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNPT1 protein function. ClinVar contains an entry for this variant (Variation ID: 209184). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2024	Observed in the heterozygous state in a patient with global developmental delay, intellectual disability, feeding difficulties, irritability, microcephaly, and dystonia who also harbored a second PNPT1 gene variant; the phase of the variants is unknown (PMID: 31752325); Observed in trans with variant of uncertain significance in the PNPT1 gene in an individual with encephalopathy, developmental delay, and hearing loss (PMID: 33199448); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31752325, 36147510, 34740920, 33199448) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 05, 2021	- -

Combined oxidative phosphorylation defect type 13

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Thr531Arg variant in PNPT1 has been identified in the compound heterozygous state by our project in one individual with Combined Oxidative Phosphorylation Deficiency (COPD). The p.Thr531Arg variant has not been reported in the literature, but it has been reported in ClinVar (Variant ID: 209184). Baylor Laboratory reported this variant in 3 probands, however only 1/3 fit the current known clinical spectrum for PNPT1. Functional evidence (PNPase Western Blot, spectrophotometric enzyme assays, Dipstick assays, OXPHOS western blot) supports a pathogenic role for this variant and is consistent with other pathogenic variants (7 publications to date). The spectrophotometric enzyme assays conducted on fibroblasts were normal, which has been observed in other PNPT1- related cases including the one published in EJHG (Alodaib, A., et al. 2016) and others (Vedrenne, V., et al. 2012, Sato, R., et al. 2017). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2015	Likely pathogenicity based on finding it three times in our laboratory in trans with another variant in affacted individuals: a 4-year-old male[with A507S] with global delays, speech articulation disorder, hypotonia; a 6-year-old male [with A507S] with spastic paraplegia, intellectual disability, anosmia, dysphagia, similarly affected sib (who is also compound heterozygous); an 18-year-old male [with V509I] 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) -

Autosomal recessive nonsyndromic hearing loss 70

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 08, 2022

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2022

The c.1592C>G (p.T531R) alteration is located in exon 19 (coding exon 19) of the PNPT1 gene. This alteration results from a C to G substitution at nucleotide position 1592, causing the threonine (T) at amino acid position 531 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.058

MutationAssessor

Pathogenic

4.2

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.95

MVP

0.75

MPC

0.66

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.97

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