rs182460499

Variant names:

• chr16-14555717-A-C
• rs182460499
• NM_002582.4:c.1263-8T>G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_002582.4(PARN):​c.1263-8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,445,260 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: PARN NM_002582.4 splice_region, intron
• Scores: Splicing: ADA: 0.0006334
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0950

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-14555717-A-C is Benign according to our data. Variant chr16-14555717-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 542672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-14555717-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000945 (144/152334) while in subpopulation NFE AF= 0.00151 (103/68034). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARN	NM_002582.4	c.1263-8T>G		splice_region_variant, intron_variant	Intron 18 of 23	ENST00000437198.7	NP_002573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARN	ENST00000437198.7	c.1263-8T>G		splice_region_variant, intron_variant	Intron 18 of 23	1	NM_002582.4	ENSP00000387911.2

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000931 AC: 151 AN: 162128 Hom.: 0 AF XY: 0.00102 AC XY: 88 AN XY: 86250

Gnomad AFR exome AF: 0.000208

Gnomad AMR exome AF: 0.000497

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000818

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.00116 AC: 1497 AN: 1292926 Hom.: 1 Cov.: 18 AF XY: 0.00119 AC XY: 769 AN XY: 643710

Gnomad4 AFR exome AF: 0.000173

Gnomad4 AMR exome AF: 0.000436

Gnomad4 ASJ exome AF: 0.0000847

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00138

Gnomad4 OTH exome AF: 0.000813

GnomAD4 genome AF: 0.000945 AC: 144 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000926 AC XY: 69 AN XY: 74506

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000937

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PARN: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 02, 2020

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.9
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00063
dbscSNV1_RF	Benign	0.042
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: rs182460499; hg19: chr16-14649574;