rs35722504

chr16-14447062-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.727

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 436149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-14447062-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PARN	NM_002582.4	c.1690G>A	p.Val564Ile	missense_variant	23/24	ENST00000437198.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PARN	ENST00000437198.7	c.1690G>A	p.Val564Ile	missense_variant	23/24	1	NM_002582.4	P1

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1026 AN: 152150 Hom.: 7 Cov.: 32

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

GnomAD3 exomes AF: 0.00861 AC: 2142 AN: 248770 Hom.: 15 AF XY: 0.00946 AC XY: 1277 AN XY: 134948

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 SAS exome AF: 0.0185

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.: 31 AF XY: 0.00967 AC XY: 7029 AN XY: 726940

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.00193

Gnomad4 NFE exome AF: 0.00957

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00674 AC: 1026 AN: 152268 Hom.: 7 Cov.: 32 AF XY: 0.00658 AC XY: 490 AN XY: 74460

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00661

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00950

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.0101 Hom.: 26

Bravo AF: 0.00629

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.000791 AC: 3

ESP6500EA AF: 0.0103 AC: 85

ExAC AF: 0.00910 AC: 1100

Asia WGS AF: 0.00664 AC: 23 AN: 3476

EpiCase AF: 0.0123

EpiControl AF: 0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 14, 2016

- -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4;C4225356:Dyskeratosis congenita, autosomal recessive 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.022	T;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
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	T
GERP RS		4.5
Varity_R		0.038
gMVP		0.096

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

Other links and lift over

dbSNP: rs35722504; hg19: chr16-14540919; COSMIC: COSV58364768;