Genetic Variant NM_021133.4:c.2172G>A (chr1-182575446-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021133.4(RNASEL):c.2172G>A(p.Lys724Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,614,144 control chromosomes in the GnomAD database, including 1,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.030 ( 113 hom., cov: 31)

Exomes 𝑓: 0.040 ( 1502 hom. )

Consequence

RNASEL
NM_021133.4 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.129

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 1-182575446-C-T is Benign according to our data. Variant chr1-182575446-C-T is described in ClinVar as [Benign]. Clinvar id is 3055991.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0295 (4498/152266) while in subpopulation NFE AF= 0.046 (3130/68014). AF 95% confidence interval is 0.0447. There are 113 homozygotes in gnomad4. There are 2222 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4498 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEL	NM_021133.4 link	c.2172G>A	p.Lys724Lys	synonymous_variant	Exon 7 of 7	ENST00000367559.7	NP_066956.1	Q05823-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEL	ENST00000367559.7 link	c.2172G>A	p.Lys724Lys	synonymous_variant	Exon 7 of 7	1	NM_021133.4	ENSP00000356530.3		Q05823-1

Frequencies

GnomAD3 genomes

AF:

0.0296

AC:

4497

AN:

152148

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00813

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.00806

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00765

Gnomad FIN

AF:

0.0727

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0460

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0308

AC:

7752

AN:

251402

Hom.:

225

AF XY:

0.0304

AC XY:

4131

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00797

Gnomad FIN exome

AF:

0.0741

Gnomad NFE exome

AF:

0.0464

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0402

AC:

58817

AN:

1461878

Hom.:

1502

Cov.:

AF XY:

0.0389

AC XY:

28316

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00618

Gnomad4 AMR exome

AF:

0.00803

Gnomad4 ASJ exome

AF:

0.0127

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00876

Gnomad4 FIN exome

AF:

0.0720

Gnomad4 NFE exome

AF:

0.0462

Gnomad4 OTH exome

AF:

0.0311

GnomAD4 genome

AF:

0.0295

AC:

4498

AN:

152266

Hom.:

113

Cov.:

AF XY:

0.0298

AC XY:

2222

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00811

Gnomad4 AMR

AF:

0.00804

Gnomad4 ASJ

AF:

0.00980

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00787

Gnomad4 FIN

AF:

0.0727

Gnomad4 NFE

AF:

0.0460

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0382

Hom.:

Bravo

AF:

0.0241

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0380

EpiControl

AF:

0.0370

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

RNASEL-related disorder

Benign:1

Jan 27, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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_noAF

Benign

-0.66

CADD

Benign

5.3

DANN

Benign

0.56

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