dbSNP rs56250729: RNASEL:p.Ile97Val (chr1-182586518-T-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_021133.4(RNASEL):c.289A>G(p.Ile97Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,610,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I97L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RNASEL
NM_021133.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

prostate cancer, hereditary, 1
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

RNASEL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17736623).

BS2

High AC in GnomAd4 at 17 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEL	NM_021133.4 link	c.289A>G	p.Ile97Val	missense_variant	Exon 2 of 7	ENST00000367559.7	NP_066956.1	Q05823-1
RNASEL	XM_047427096.1 link	c.289A>G	p.Ile97Val	missense_variant	Exon 2 of 7		XP_047283052.1
RNASEL	XM_047427106.1 link	c.289A>G	p.Ile97Val	missense_variant	Exon 2 of 6		XP_047283062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEL	ENST00000367559.7 link	c.289A>G	p.Ile97Val	missense_variant	Exon 2 of 7	1	NM_021133.4	ENSP00000356530.3		Q05823-1
RNASEL	ENST00000539397.1 link	c.289A>G	p.Ile97Val	missense_variant	Exon 2 of 6	2		ENSP00000440844.1		Q05823-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000280

AC:

AN:

250096

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000891

AC:

AN:

1458570

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

725040

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

33266

American (AMR)

AF:

0.00

AC:

AN:

44446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109604

Other (OTH)

AF:

0.00

AC:

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

T;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.4

L;L

PhyloP100

1.6

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.62

N;N

REVEL

Benign

0.24

Sift

Uncertain

0.026

D;D

Sift4G

Benign

0.10

T;T

Polyphen

1.0

D;.

Vest4

0.36

MutPred

0.36

Gain of phosphorylation at T94 (P = 0.1249);Gain of phosphorylation at T94 (P = 0.1249);

MVP

0.76

MPC

0.26

ClinPred

0.13

GERP RS

4.7

Varity_R

0.16

gMVP

0.21

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over