1-182582202-A-C

Position:

• chr1-182582202-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021133.4(RNASEL):​c.1623T>G​(p.Asp541Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 1,613,892 control chromosomes in the GnomAD database, including 243,429 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.49 (19281 hom., cov: 33)
  • Exomes 𝑓: 0.55 (224148 hom.)
• Consequence: RNASEL NM_021133.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.27

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3087199E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEL	NM_021133.4	c.1623T>G	p.Asp541Glu	missense_variant	4/7	ENST00000367559.7	NP_066956.1
RNASEL	XM_047427096.1	c.1623T>G	p.Asp541Glu	missense_variant	4/7		XP_047283052.1
RNASEL	XM_047427106.1	c.1623T>G	p.Asp541Glu	missense_variant	4/6		XP_047283062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEL	ENST00000367559.7	c.1623T>G	p.Asp541Glu	missense_variant	4/7	1	NM_021133.4	ENSP00000356530.3
RNASEL	ENST00000539397.1	c.1623T>G	p.Asp541Glu	missense_variant	4/6	2		ENSP00000440844.1

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74663 AN: 151984 Hom.: 19281 Cov.: 33

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.492

GnomAD3 exomes AF: 0.540 AC: 134299 AN: 248780 Hom.: 37156 AF XY: 0.543 AC XY: 73147 AN XY: 134670

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.480

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.723

Gnomad SAS exome AF: 0.499

Gnomad FIN exome AF: 0.607

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.551 AC: 805012 AN: 1461790 Hom.: 224148 Cov.: 61 AF XY: 0.549 AC XY: 399369 AN XY: 727204

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.474

Gnomad4 ASJ exome AF: 0.489

Gnomad4 EAS exome AF: 0.713

Gnomad4 SAS exome AF: 0.499

Gnomad4 FIN exome AF: 0.605

Gnomad4 NFE exome AF: 0.560

Gnomad4 OTH exome AF: 0.534

GnomAD4 genome AF: 0.491 AC: 74697 AN: 152102 Hom.: 19281 Cov.: 33 AF XY: 0.494 AC XY: 36754 AN XY: 74346

Gnomad4 AFR AF: 0.324

Gnomad4 AMR AF: 0.462

Gnomad4 ASJ AF: 0.462

Gnomad4 EAS AF: 0.725

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.608

Gnomad4 NFE AF: 0.565

Gnomad4 OTH AF: 0.495

Alfa AF: 0.549 Hom.: 51562

Bravo AF: 0.471

TwinsUK AF: 0.556 AC: 2062

ALSPAC AF: 0.555 AC: 2138

ESP6500AA AF: 0.329 AC: 1451

ESP6500EA AF: 0.545 AC: 4690

ExAC AF: 0.538 AC: 65311

Asia WGS AF: 0.598 AC: 2078 AN: 3478

EpiCase AF: 0.561

EpiControl AF: 0.558

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0090
DANN	Benign	0.20
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.052	T;T
MetaRNN	Benign	0.0000013	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.41	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.86	N;N
REVEL	Benign	0.0060
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.015
MutPred		0.14		Loss of ubiquitination at K543 (P = 0.1037);Loss of ubiquitination at K543 (P = 0.1037);
MPC		0.051
ClinPred		0.0046	T
GERP RS		-5.6
Varity_R		0.065
gMVP		0.082

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: rs627928; hg19: chr1-182551337; COSMIC: COSV62377403;