rs35722504

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002582.4(PARN):c.1690G>A(p.Val564Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00912 in 1,613,602 control chromosomes in the GnomAD database, including 108 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V564A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0067 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0094 ( 101 hom. )

Consequence

PARN
NM_002582.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.727

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

dyskeratosis congenita, autosomal recessive 6
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PARN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002854675).

BP6

Variant 16-14447062-C-T is Benign according to our data. Variant chr16-14447062-C-T is described in ClinVar as Benign. ClinVar VariationId is 436149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00674 (1026/152268) while in subpopulation SAS AF = 0.0203 (98/4828). AF 95% confidence interval is 0.017. There are 7 homozygotes in GnomAd4. There are 490 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARN	NM_002582.4 link	c.1690G>A	p.Val564Ile	missense_variant	Exon 23 of 24	ENST00000437198.7	NP_002573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARN	ENST00000437198.7 link	c.1690G>A	p.Val564Ile	missense_variant	Exon 23 of 24	1	NM_002582.4	ENSP00000387911.2

Frequencies

GnomAD3 genomes

AF:

0.00674

AC:

1026

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00662

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0203

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00951

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00861

AC:

2142

AN:

248770

AF XY:

0.00946

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00363

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00163

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.00937

AC:

13698

AN:

1461334

Hom.:

101

Cov.:

AF XY:

0.00967

AC XY:

7029

AN XY:

726940

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

33476

American (AMR)

AF:

0.00371

AC:

166

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

548

AN:

26120

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.0173

AC:

1493

AN:

86208

European-Finnish (FIN)

AF:

0.00193

AC:

103

AN:

53390

Middle Eastern (MID)

AF:

0.0175

AC:

101

AN:

5768

European-Non Finnish (NFE)

AF:

0.00957

AC:

10633

AN:

1111610

Other (OTH)

AF:

0.0102

AC:

613

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

595

1189

1784

2378

2973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

384

768

1152

1536

1920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00674

AC:

1026

AN:

152268

Hom.:

Cov.:

AF XY:

0.00658

AC XY:

490

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41554

American (AMR)

AF:

0.00661

AC:

101

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0203

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00950

AC:

646

AN:

68026

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00928

Hom.:

Bravo

AF:

0.00629

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.000791

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00910

AC:

1100

Asia WGS

AF:

0.00664

AC:

AN:

3476

EpiCase

AF:

0.0123

EpiControl

AF:

0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 14, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.022

T;.;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.65

T;T;T;T

MetaRNN

Benign

0.0029

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

L;.;.;.

PhyloP100

0.73

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.42

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.079

T;T;T;T

Sift4G

Benign

0.21

T;T;T;T

Polyphen

0.0060

B;.;.;.

Vest4

0.054

MVP

0.19

MPC

0.11

ClinPred

0.0087

GERP RS

4.5

Varity_R

0.038

gMVP

0.096

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over