1-182581355-C-A

Position:

• chr1-182581355-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021133.4(RNASEL):​c.1775G>T​(p.Arg592Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R592H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RNASEL NM_021133.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEL	NM_021133.4	c.1775G>T	p.Arg592Leu	missense_variant, splice_region_variant	5/7	ENST00000367559.7	NP_066956.1
RNASEL	XM_047427096.1	c.1775G>T	p.Arg592Leu	missense_variant, splice_region_variant	5/7		XP_047283052.1
RNASEL	XM_047427106.1	c.1775G>T	p.Arg592Leu	missense_variant, splice_region_variant	5/6		XP_047283062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEL	ENST00000367559.7	c.1775G>T	p.Arg592Leu	missense_variant, splice_region_variant	5/7	1	NM_021133.4	ENSP00000356530.3
RNASEL	ENST00000539397.1	c.1775G>T	p.Arg592Leu	missense_variant, splice_region_variant	5/6	2		ENSP00000440844.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.85	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.69
MutPred		0.47		Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);
MVP		0.79
MPC		0.38
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.83
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35896902; hg19: chr1-182550490;