rs35405862

Positions:

chr2-55671351-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000447944.7(PNPT1):c.944A>G(p.Lys315Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000784 in 1,542,178 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 9 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 6 hom. )

Consequence

PNPT1
ENST00000447944.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.03

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010453165).

BP6

Variant 2-55671351-T-C is Benign according to our data. Variant chr2-55671351-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 214999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00453 (690/152342) while in subpopulation AFR AF= 0.0161 (669/41584). AF 95% confidence interval is 0.0151. There are 9 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PNPT1	NM_033109.5 linkuse as main transcript	c.944A>G	p.Lys315Arg	missense_variant	11/28	ENST00000447944.7	NP_149100.2
PNPT1	XM_005264629.3 linkuse as main transcript	c.704A>G	p.Lys235Arg	missense_variant	11/28		XP_005264686.1
PNPT1	XM_017005172.2 linkuse as main transcript	c.704A>G	p.Lys235Arg	missense_variant	10/27		XP_016860661.1
PNPT1	XM_047446161.1 linkuse as main transcript	c.944A>G	p.Lys315Arg	missense_variant	11/20		XP_047302117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PNPT1	ENST00000447944.7 linkuse as main transcript	c.944A>G	p.Lys315Arg	missense_variant	11/28	1	NM_033109.5	ENSP00000400646	P1
PNPT1	ENST00000415374.5 linkuse as main transcript	c.944A>G	p.Lys315Arg	missense_variant, NMD_transcript_variant	11/29	5		ENSP00000393953
PNPT1	ENST00000415489.1 linkuse as main transcript	c.20A>G	p.Lys7Arg	missense_variant, NMD_transcript_variant	1/8	3		ENSP00000411057
PNPT1	ENST00000260604.8 linkuse as main transcript	c.*499A>G		3_prime_UTR_variant, NMD_transcript_variant	10/27	5		ENSP00000260604

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

686

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00100

AC:

216

AN:

215022

Hom.:

AF XY:

0.000716

AC XY:

AN XY:

117342

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.000436

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:

0.0000293

Gnomad OTH exome

AF:

0.000202

GnomAD4 exome

AF:

0.000373

AC:

519

AN:

1389836

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

215

AN XY:

691080

show subpopulations

Gnomad4 AFR exome

AF:

0.0149

Gnomad4 AMR exome

AF:

0.000592

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:

0.00000279

Gnomad4 OTH exome

AF:

0.000822

GnomAD4 genome

AF:

0.00453

AC:

690

AN:

152342

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0161

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.00506

ESP6500AA

AF:

0.0153

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00129

AC:

157

Asia WGS

AF:

0.000578

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 21, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PNPT1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

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

0.081

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.76

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.0

REVEL

Benign

0.15

Sift

Benign

0.15

Sift4G

Benign

0.41

Polyphen

0.81

Vest4

0.56

MVP

0.66

MPC

0.25

ClinPred

0.057

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.40

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

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