1-182582234-C-T

Position:

• chr1-182582234-C-T

Variant summary

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

The ENST00000367559.7(RNASEL):​c.1591G>A​(p.Val531Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNASEL ENST00000367559.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78

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.1591G>A	p.Val531Met	missense_variant	4/7	ENST00000367559.7	NP_066956.1
RNASEL	XM_047427096.1	c.1591G>A	p.Val531Met	missense_variant	4/7		XP_047283052.1
RNASEL	XM_047427106.1	c.1591G>A	p.Val531Met	missense_variant	4/6		XP_047283062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEL	ENST00000367559.7	c.1591G>A	p.Val531Met	missense_variant	4/7	1	NM_021133.4	ENSP00000356530	P1
RNASEL	ENST00000539397.1	c.1591G>A	p.Val531Met	missense_variant	4/6	2		ENSP00000440844

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Prostate cancer, hereditary, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

This variant results in a change from valine to methionine at codon 531. This variant was not identified in the literature nor was it identified in ClinVar or Cosmic. In-silico predictions show Pathogenic computational verdict based on 8 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster, PolyPhen and SIFT vs 5 benign predictions from BayesDel_addAF, DEOGEN2, LIST-S2, MVP and PrimateAI. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. Therefore, this variant is classified as a variant of uncertain -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.78	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.46
MutPred		0.76		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.50
MPC		0.35
ClinPred		0.94	D
GERP RS		4.2
Varity_R		0.32
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-182551369;