rs34928857

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033109.5(PNPT1):c.688G>C(p.Glu230Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,572,468 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

PNPT1
NM_033109.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 7.49

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042710304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PNPT1	NM_033109.5 linkuse as main transcript	c.688G>C	p.Glu230Gln	missense_variant	9/28	ENST00000447944.7	NP_149100.2
PNPT1	XM_005264629.3 linkuse as main transcript	c.448G>C	p.Glu150Gln	missense_variant	9/28		XP_005264686.1
PNPT1	XM_017005172.2 linkuse as main transcript	c.448G>C	p.Glu150Gln	missense_variant	8/27		XP_016860661.1
PNPT1	XM_047446161.1 linkuse as main transcript	c.688G>C	p.Glu230Gln	missense_variant	9/20		XP_047302117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PNPT1	ENST00000447944.7 linkuse as main transcript	c.688G>C	p.Glu230Gln	missense_variant	9/28	1	NM_033109.5	ENSP00000400646	P1
PNPT1	ENST00000415374.5 linkuse as main transcript	c.688G>C	p.Glu230Gln	missense_variant, NMD_transcript_variant	9/29	5		ENSP00000393953
PNPT1	ENST00000260604.8 linkuse as main transcript	c.*243G>C		3_prime_UTR_variant, NMD_transcript_variant	8/27	5		ENSP00000260604

Frequencies

GnomAD3 genomes

AF:

0.00161

AC:

245

AN:

151784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00551

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000447

AC:

AN:

207900

Hom.:

AF XY:

0.000351

AC XY:

AN XY:

113864

show subpopulations

Gnomad AFR exome

AF:

0.00552

Gnomad AMR exome

AF:

0.000531

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:

0.0000100

Gnomad OTH exome

AF:

0.000429

GnomAD4 exome

AF:

0.000133

AC:

189

AN:

1420566

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

706252

show subpopulations

Gnomad4 AFR exome

AF:

0.00489

Gnomad4 AMR exome

AF:

0.000388

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.000394

GnomAD4 genome

AF:

0.00162

AC:

246

AN:

151902

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

114

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.00552

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000157

Hom.:

Bravo

AF:

0.00172

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000470

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2024	Observed with a second PNPT1 variant on the opposite allele (in trans) in a patient with arm and leg weakness, developmental delay, scoliosis, epilepsy, and sensory axonal polyneuropathy (PMID: 35303589); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35303589) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Combined oxidative phosphorylation defect type 13

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 25, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

PNPT1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2020

This variant is classified as likely 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

Pathogenic

0.84

BayesDel_addAF

Benign

-0.0021

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.046

MetaRNN

Benign

0.043

MetaSVM

Uncertain

0.14

MutationAssessor

Pathogenic

4.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.41

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.94

MVP

0.73

MPC

0.62

ClinPred

0.17

GERP RS

5.7

Varity_R

0.93

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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