chr1-204155157-C-CT

Variant names:

• chr1-204155157-C-CT
• NM_000537.4:c.1079dupA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000537.4(REN):​c.1079dupA​(p.Leu361AlafsTer34) variant causes a frameshift 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: REN NM_000537.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.735

Genes affected

REN (HGNC:9958): (renin) This gene encodes renin, an aspartic protease that is secreted by the kidneys. Renin is a part of the renin-angiotensin-aldosterone system involved in regulation of blood pressure, and electrolyte balance. This enzyme catalyzes the first step in the activation pathway of angiotensinogen by cleaving angiotensinogen to form angiotensin I, which is then converted to angiotensin II by angiotensin I converting enzyme. This cascade can result in aldosterone release, narrowing of blood vessels, and increase in blood pressure as angiotension II is a vasoconstrictive peptide. Transcript variants that encode different protein isoforms and that arise from alternative splicing and the use of alternative promoters have been described, but their full-length nature has not been determined. Mutations in this gene have been shown to cause hyperuricemic nephropathy familial juvenile 2, familial hyperproreninemia, and renal tubular dysgenesis. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.116 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-204155157-C-CT is Pathogenic according to our data. Variant chr1-204155157-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3384161.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REN	NM_000537.4	c.1079dupA	p.Leu361AlafsTer34	frameshift_variant	Exon 10 of 10	ENST00000272190.9	NP_000528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REN	ENST00000272190.9	c.1079dupA	p.Leu361AlafsTer34	frameshift_variant	Exon 10 of 10	1	NM_000537.4	ENSP00000272190.8
REN	ENST00000638118.1	c.965dupA	p.Leu323AlafsTer34	frameshift_variant	Exon 12 of 12	5		ENSP00000490307.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 2 Pathogenic:1

Jun 14, 2024

Genetics laboratory, Department of Obstetrics & Gynae, Institute of Kidney Diseases & Research Centre Dr. H.L. Trivedi Institute Of Transplantation Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A heterozygous frameshift insertion variant c.1079_1080insA in REN gene (chr1:204124285; Depth:139x) was detected. The variant results from insertion of one nucleotide at nucleotide position 1079th, causing a translational frameshift with a predicted alternate stop codon (p.Leu361AlafsTer34). This variant is not observed in Clinvar, 1000 genomes, topmed and gnomAD database. Based on the aforementioned evidence, the variant is classified as a likely pathogenic based on the ACMG-AMP classification system. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr1-204124285;