rs200103366

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002582.4(PARN):c.466G>T(p.Ala156Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00027 in 1,604,418 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A156T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

PARN
NM_002582.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.59

Variant links:

Genes affected

PARN (HGNC:8609): (poly(A)-specific ribonuclease) The protein encoded by this gene is a 3'-exoribonuclease, with similarity to the RNase D family of 3'-exonucleases. It prefers poly(A) as the substrate, hence, efficiently degrades poly(A) tails of mRNAs. Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs. This protein is also involved in silencing of certain maternal mRNAs during oocyte maturation and early embryonic development, as well as in nonsense-mediated decay (NMD) of mRNAs that contain premature stop codons. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

PARN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10150367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PARN	NM_002582.4 linkuse as main transcript	c.466G>T	p.Ala156Ser	missense_variant	7/24	ENST00000437198.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PARN	ENST00000437198.7 linkuse as main transcript	c.466G>T	p.Ala156Ser	missense_variant	7/24	1	NM_002582.4	P1	O95453-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000273

AC:

AN:

249214

Hom.:

AF XY:

0.000259

AC XY:

AN XY:

135206

show subpopulations

Gnomad AFR exome

AF:

0.000129

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:

0.000371

Gnomad NFE exome

AF:

0.000505

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000260

AC:

378

AN:

1452246

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

198

AN XY:

723108

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

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:

0.000468

Gnomad4 NFE exome

AF:

0.000307

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000361

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000542

Hom.:

Bravo

AF:

0.000193

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000605

AC:

ExAC

AF:

0.000372

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 17, 2021

DNA sequence analysis of the PARN gene demonstrated a sequence change, c.466G>T, in exon 7 that results in an amino acid change, p.Ala156Ser. This sequence change has been described in the gnomAD database with a frequency of 0.069% in the non-Finnish European subpopulation (dbSNP rs200103366). The p.Ala156Ser change affects a highly conserved amino acid residue located in a domain of the PARN protein that is known to be functional. The p.Ala156Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with PARN-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ala156Ser change remains unknown at this time. -

Dyskeratosis congenita, autosomal recessive 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 21, 2018

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

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4;C4225356:Dyskeratosis congenita, autosomal recessive 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 156 of the PARN protein (p.Ala156Ser). This variant is present in population databases (rs200103366, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with PARN-related conditions. ClinVar contains an entry for this variant (Variation ID: 569031). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

PARN: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.016

T;.;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.4

L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.49

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.64

P;.;.

Vest4

0.24

MVP

0.21

MPC

0.14

ClinPred

0.031

GERP RS

4.5

Varity_R

0.081

gMVP

0.33

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