1-182581355-C-G

Variant names:

• chr1-182581355-C-G
• NM_021133.4:c.1775G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021133.4(RNASEL):​c.1775G>C​(p.Arg592Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R592H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEL	NM_021133.4	c.1775G>C	p.Arg592Pro	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000367559.7	NP_066956.1
RNASEL	XM_047427096.1	c.1775G>C	p.Arg592Pro	missense_variant, splice_region_variant	Exon 5 of 7		XP_047283052.1
RNASEL	XM_047427106.1	c.1775G>C	p.Arg592Pro	missense_variant, splice_region_variant	Exon 5 of 6		XP_047283062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEL	ENST00000367559.7	c.1775G>C	p.Arg592Pro	missense_variant, splice_region_variant	Exon 5 of 7	1	NM_021133.4	ENSP00000356530.3
RNASEL	ENST00000539397.1	c.1775G>C	p.Arg592Pro	missense_variant, splice_region_variant	Exon 5 of 6	2		ENSP00000440844.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.78
MutPred		0.52		Loss of MoRF binding (P = 0.0094);Loss of MoRF binding (P = 0.0094);
MVP		0.82
MPC		0.41
ClinPred		0.90	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: -7

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-182550490;