Variant 16-14436756-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002582.4(PARN):c.1881C>A(p.Asn627Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,442,490 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

PARN
NM_002582.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.378

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:

PARN (HGNC:):

PARN links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07505697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARN	NM_002582.4 linkuse as main transcript	c.1881C>A	p.Asn627Lys	missense_variant	24/24	ENST00000437198.7	NP_002573.1	O95453-1B3KN69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARN	ENST00000437198.7 linkuse as main transcript	c.1881C>A	p.Asn627Lys	missense_variant	24/24	1	NM_002582.4	ENSP00000387911.2		O95453-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000465

AC:

AN:

214848

Hom.:

AF XY:

0.00000865

AC XY:

AN XY:

115628

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:

0.0000377

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000416

AC:

AN:

1442490

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

715456

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000725

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2022

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 627 of the PARN protein (p.Asn627Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PARN-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.015

T;.;.;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.53

T;T;T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.075

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.29

N;N;N;N

REVEL

Benign

0.063

Sift

Benign

0.082

T;T;T;T

Sift4G

Benign

0.92

T;T;T;T

Polyphen

0.0010

B;.;.;.

Vest4

0.086

MutPred

0.17

Gain of ubiquitination at N627 (P = 0.0018);.;.;.;

MVP

0.28

MPC

0.16

ClinPred

0.027

GERP RS

2.2

Varity_R

0.039

gMVP

0.074

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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