NM_021133.4:c.1385G>A

Variant names:

• chr1-182585422-C-T
• rs486907
• NM_021133.4:c.1385G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021133.4(RNASEL):​c.1385G>A​(p.Arg462Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,613,854 control chromosomes in the GnomAD database, including 94,567 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6971 hom., cov: 32)
  • Exomes 𝑓: 0.34 (87596 hom.)
• Consequence: RNASEL NM_021133.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1 O:1
• Conservation: PhyloP100: 0.229
• Publications: 214 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041000247).
• BP6: Variant 1-182585422-C-T is Benign according to our data. Variant chr1-182585422-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 13006.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021133.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEL	NM_021133.4	MANE Select	c.1385G>A	p.Arg462Gln	missense	Exon 2 of 7	NP_066956.1	Q05823-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEL	ENST00000367559.7	TSL:1 MANE Select	c.1385G>A	p.Arg462Gln	missense	Exon 2 of 7	ENSP00000356530.3	Q05823-1
	RNASEL	ENST00000946546.1		c.1385G>A	p.Arg462Gln	missense	Exon 2 of 7	ENSP00000616605.1
	RNASEL	ENST00000890859.1		c.1385G>A	p.Arg462Gln	missense	Exon 2 of 7	ENSP00000560918.1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42890 AN: 151884 Hom.: 6974 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.300

GnomAD2 exomes AF: 0.305 AC: 76756 AN: 251298 AF XY: 0.315

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.233

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.369

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.340 AC: 497143 AN: 1461852 Hom.: 87596 Cov.: 45 AF XY: 0.340 AC XY: 247265 AN XY: 727232

African (AFR) AF: 0.111 AC: 3730 AN: 33480

American (AMR) AF: 0.179 AC: 7986 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 8351 AN: 26134

East Asian (EAS) AF: 0.220 AC: 8722 AN: 39698

South Asian (SAS) AF: 0.294 AC: 25371 AN: 86256

European-Finnish (FIN) AF: 0.380 AC: 20289 AN: 53416

Middle Eastern (MID) AF: 0.288 AC: 1660 AN: 5768

European-Non Finnish (NFE) AF: 0.361 AC: 401686 AN: 1111980

Other (OTH) AF: 0.320 AC: 19348 AN: 60396

GnomAD4 genome AF: 0.282 AC: 42892 AN: 152002 Hom.: 6971 Cov.: 32 AF XY: 0.282 AC XY: 20959 AN XY: 74290

African (AFR) AF: 0.123 AC: 5095 AN: 41496

American (AMR) AF: 0.251 AC: 3827 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1058 AN: 3472

East Asian (EAS) AF: 0.235 AC: 1214 AN: 5156

South Asian (SAS) AF: 0.292 AC: 1405 AN: 4812

European-Finnish (FIN) AF: 0.384 AC: 4049 AN: 10534

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25185 AN: 67952

Other (OTH) AF: 0.301 AC: 635 AN: 2110

Alfa AF: 0.334 Hom.: 30228

Bravo AF: 0.262

TwinsUK AF: 0.358 AC: 1326

ALSPAC AF: 0.348 AC: 1341

ESP6500AA AF: 0.133 AC: 587

ESP6500EA AF: 0.356 AC: 3065

ExAC AF: 0.309 AC: 37496

Asia WGS AF: 0.283 AC: 986 AN: 3478

EpiCase AF: 0.362

EpiControl AF: 0.366

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer (1)
-	1	-	Prostate cancer, hereditary, 1 (1)
-	-	-	Prostate cancer susceptibility (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.23
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.074
Sift	Benign	0.030	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.071
MPC		0.12
ClinPred		0.016	T
GERP RS		0.056
Varity_R		0.10
gMVP		0.23
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs486907; hg19: chr1-182554557; COSMIC: COSV62376340;