rs74315364

Positions:

chr1-182586014-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_021133.4(RNASEL):c.793G>T(p.Glu265Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,614,092 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 16 hom. )

Consequence

RNASEL
NM_021133.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:3

Conservation

PhyloP100: 0.951

Variant links:

Genes affected

RNASEL (HGNC:10050): (ribonuclease L) This gene encodes a component of the interferon-regulated 2-5A system that functions in the antiviral and antiproliferative roles of interferons. The protein is involved in innate immunity and is active against multiple RNA viruses, including the influenza and SARS-CoV-2 viruses. Mutations in this gene have been associated with predisposition to prostate cancer and this gene is a candidate for the hereditary prostate cancer 1 (HPC1) allele. [provided by RefSeq, Nov 2021]

RNASEL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant 1-182586014-C-A is Benign according to our data. Variant chr1-182586014-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13004.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 496 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RNASEL	NM_021133.4 linkuse as main transcript	c.793G>T	p.Glu265Ter	stop_gained	2/7	ENST00000367559.7	NP_066956.1
RNASEL	XM_047427096.1 linkuse as main transcript	c.793G>T	p.Glu265Ter	stop_gained	2/7		XP_047283052.1
RNASEL	XM_047427106.1 linkuse as main transcript	c.793G>T	p.Glu265Ter	stop_gained	2/6		XP_047283062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEL	ENST00000367559.7 linkuse as main transcript	c.793G>T	p.Glu265Ter	stop_gained	2/7	1	NM_021133.4	ENSP00000356530	P1	Q05823-1
RNASEL	ENST00000539397.1 linkuse as main transcript	c.793G>T	p.Glu265Ter	stop_gained	2/6	2		ENSP00000440844		Q05823-2

Frequencies

GnomAD3 genomes

AF:

0.00325

AC:

495

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00582

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00401

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00362

AC:

901

AN:

249190

Hom.:

AF XY:

0.00377

AC XY:

508

AN XY:

134824

show subpopulations

Gnomad AFR exome

AF:

0.000559

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00360

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.00818

Gnomad NFE exome

AF:

0.00500

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00373

AC:

5453

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

2722

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00228

Gnomad4 ASJ exome

AF:

0.00367

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.00810

Gnomad4 NFE exome

AF:

0.00397

Gnomad4 OTH exome

AF:

0.00399

GnomAD4 genome

AF:

0.00326

AC:

496

AN:

152302

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

234

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00582

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00622

Gnomad4 NFE

AF:

0.00401

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00368

Hom.:

Bravo

AF:

0.00313

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00398

AC:

483

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00376

EpiControl

AF:

0.00391

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Prostate cancer, hereditary, 1

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	RNASEL: BS1, BS2 -

Malignant tumor of prostate

Pathogenic:1

Likely pathogenic, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

NM_021133.3:c.793G>T in the RNASEL gene has an allele frequency of 0.008 in European (Finnish) subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.793G>T(p.Glu265*) was segregated in four affected brothers from a family suffering from prostate canser (PMID: 11799394). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PP1_Moderate. -

RNASEL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.40

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.59

MutationTaster

Benign

1.0

A;A;A

Vest4

0.53

GERP RS

3.2

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

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