1-182586518-T-G

Variant names:

• chr1-182586518-T-G
• rs56250729
• NM_021133.4:c.289A>C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_021133.4(RNASEL):​c.289A>C​(p.Ile97Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00905 in 1,610,920 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (87 hom.)
• Consequence: RNASEL NM_021133.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.56

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00963223).
• BP6: Variant 1-182586518-T-G is Benign according to our data. Variant chr1-182586518-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 806296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 834 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEL	NM_021133.4	c.289A>C	p.Ile97Leu	missense_variant	Exon 2 of 7	ENST00000367559.7	NP_066956.1
RNASEL	XM_047427096.1	c.289A>C	p.Ile97Leu	missense_variant	Exon 2 of 7		XP_047283052.1
RNASEL	XM_047427106.1	c.289A>C	p.Ile97Leu	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	c.289A>C	p.Ile97Leu	missense_variant	Exon 2 of 7	1	NM_021133.4	ENSP00000356530.3
RNASEL	ENST00000539397.1	c.289A>C	p.Ile97Leu	missense_variant	Exon 2 of 6	2		ENSP00000440844.1

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 834 AN: 152234 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00985

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00663 AC: 1659 AN: 250096 Hom.: 13 AF XY: 0.00689 AC XY: 932 AN XY: 135196

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00226

Gnomad FIN exome AF: 0.00658

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00625

GnomAD4 exome AF: 0.00943 AC: 13748 AN: 1458568 Hom.: 87 Cov.: 35 AF XY: 0.00924 AC XY: 6696 AN XY: 725038

Gnomad4 AFR exome AF: 0.00159

Gnomad4 AMR exome AF: 0.00196

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00247

Gnomad4 FIN exome AF: 0.00678

Gnomad4 NFE exome AF: 0.0114

Gnomad4 OTH exome AF: 0.00628

GnomAD4 genome AF: 0.00547 AC: 834 AN: 152352 Hom.: 5 Cov.: 32 AF XY: 0.00523 AC XY: 390 AN XY: 74506

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.00985

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00849 Hom.: 1

Bravo AF: 0.00517

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00769 AC: 934

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00823

EpiControl AF: 0.00848

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNASEL: BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T;.
Eigen	Benign	0.030
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0096	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.51	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.66	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.033	D;D
Sift4G	Benign	0.21	T;T
Polyphen		1.0	D;.
Vest4		0.35
MVP		0.76
MPC		0.12
ClinPred		0.033	T
GERP RS		4.7
Varity_R		0.31
gMVP		0.44

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

Other links and lift over

dbSNP: rs56250729; hg19: chr1-182555653;