chr16-14627161-T-C

Position:

chr16-14627161-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PP5

The NM_002582.4(PARN):c.272A>G(p.Tyr91Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000548 in 1,605,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

PARN
NM_002582.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 6.73

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.751

PP5

Variant 16-14627161-T-C is Pathogenic according to our data. Variant chr16-14627161-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542669.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARN	NM_002582.4 linkuse as main transcript	c.272A>G	p.Tyr91Cys	missense_variant	5/24	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.272A>G	p.Tyr91Cys	missense_variant	5/24	1	NM_002582.4	ENSP00000387911.2		O95453-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000697

AC:

AN:

243878

Hom.:

AF XY:

0.0000681

AC XY:

AN XY:

132178

show subpopulations

Gnomad AFR exome

AF:

0.000134

Gnomad AMR exome

AF:

0.000177

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.0000543

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000509

AC:

AN:

1453486

Hom.:

Cov.:

AF XY:

0.0000387

AC XY:

AN XY:

723262

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000181

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000351

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000488

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000889

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

PARN-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 05, 2024

Variant summary: PARN c.272A>G (p.Tyr91Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7e-05 in 243878 control chromosomes. c.272A>G has been reported in the literature in trans along with a pathogenic variant in PARN in two siblings affected with Hoyeraal-Hreidarsson syndrome, other family members carrying this variant reported healthy but had reduced levels of lymphocyte telomeres (example, Dodson_2019). The variant was also reported as a de novo change in one individual from a cohort of Autism patients, without sufficient information for independent analysis (Zhou_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal deadenylation activity in vitro (Dodson_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31448843, 35982159). ClinVar contains an entry for this variant (Variation ID: 542669). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Dyskeratosis congenita, autosomal recessive 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro

Bertuch Lab, Baylor College of Medicine

May 15, 2019

PARN is a ribodeadenylase. Biallelic PARN variants have been reported in 9 cases of Hoyeraal-Hreidarsson syndrome (HH)/dyskeratosis congenita. Monoallelic PARN variants are associated with IPF and more than 50 cases have been reported. This rare missense variant, p.Y91C, and novel insertion variant, p.I274*, were found in trans in two siblings with HH. Unaffected family members did not have both variants. Functional studies showed that PARN p.Y91C had reduced deadenylase activity and the p.I274* transcript likely underwent NMD. Studies with patient-derived samples showed the expected alteration of PARN target RNAs in one affected sibling. Telomere lengths were extremely short for both affected siblings. However, monoallelic variant carriers had variable telomere length, indicating incomplete penetrance of short telomeres in PARN variant carriers. In summary, this variant has strong evidence for being pathogenic according to ACMG 2015 guidelines and functional data, segregation data, and allelic data. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Mar 09, 2022

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 05, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 91 of the PARN protein (p.Tyr91Cys). This variant is present in population databases (rs201765587, gnomAD 0.02%). This missense change has been observed in individual(s) with Hoyeraal Hreidarsson syndrome (PMID: 31448843; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 542669). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PARN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PARN function (PMID: 31448843). For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 14, 2019

- -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jul 05, 2023

The PARN c.272A>G variant is classified as VUS (PS3_Moderate) The PARN c.272A>G variant is a single nucleotide change in exon 5/24 of the PARN gene, which is predicted to change the amino acid tyrosine at position 91 in the protein to cysteine. This variant is present at low frequency in population databases (gnomAD allele frequency = 0.0091%; 14 het and 0 hom in 152186 sequenced alleles; highest frequency = 0.019%, East Asian population) (PM2 not met). Computational predictions provide conflicting interpretations of pathogenicity for this variant (PP3 and BP4 not met). Functional studies showed that the p.(Tyr91Cys) variant had reduced deadenylase activity (10-fold lower than WT). The Y91C-mutated PARN polypeptide was perturbed in its deadenylation activity and suggest that the PARN-mediated deadenylation activity in individuals in this pedigree carrying the mutation was affected. However, the affected pedigree shows pseudo-dominant inheritance, and the heterozygous carriers of the Y91C variant only displayed reduced telomeres, without bone marrow failure (Dodson et al, 2019; PMID:31448843). (PS3_moderate). The variant has been reported in dbSNP (rs201765587) and in the HGMD database: CM1918160. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 542669). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.054

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Uncertain

-0.079

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-8.1

D;D

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.90

MVP

0.64

MPC

0.69

ClinPred

0.95

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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