rs59687658

Positions:

• chr16-14599898-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000437198.7(PARN):​c.840+6T>C variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00144 in 1,586,058 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (24 hom.)
• Consequence: PARN ENST00000437198.7 splice_donor_region, intron
• Scores: Splicing: ADA: 0.5625
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 5.42

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 16-14599898-A-G is Benign according to our data. Variant chr16-14599898-A-G is described in ClinVar as [Benign]. Clinvar id is 436151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-14599898-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0023 (347/151048) while in subpopulation EAS AF= 0.016 (83/5186). AF 95% confidence interval is 0.0132. There are 4 homozygotes in gnomad4. There are 221 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARN	NM_002582.4	c.840+6T>C		splice_donor_region_variant, intron_variant		ENST00000437198.7	NP_002573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARN	ENST00000437198.7	c.840+6T>C		splice_donor_region_variant, intron_variant		1	NM_002582.4	ENSP00000387911	P1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 348 AN: 150936 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00238 AC: 577 AN: 242122 Hom.: 8 AF XY: 0.00225 AC XY: 295 AN XY: 131288

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.000608

Gnomad EAS exome AF: 0.0138

Gnomad SAS exome AF: 0.00426

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000386

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.00135 AC: 1932 AN: 1435010 Hom.: 24 Cov.: 26 AF XY: 0.00140 AC XY: 1003 AN XY: 714954

Gnomad4 AFR exome AF: 0.000250

Gnomad4 AMR exome AF: 0.00388

Gnomad4 ASJ exome AF: 0.000620

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.00417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000347

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00230 AC: 347 AN: 151048 Hom.: 4 Cov.: 32 AF XY: 0.00299 AC XY: 221 AN XY: 73866

Gnomad4 AFR AF: 0.000396

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0160

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.00198

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pulmonary fibrosis;na:Familial Interstitial Pneumonia Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 03, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

PARN: BS1, BS2 -

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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.56
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: -42

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs59687658; hg19: chr16-14693755;