rs6693954

Variant names:

• chr1-204163510-T-A
• rs6693954
• NM_000537.4:c.99-1347A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000537.4(REN):​c.99-1347A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 152,126 control chromosomes in the GnomAD database, including 8,370 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8370 hom., cov: 32)
• Consequence: REN NM_000537.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0150
• Publications: 13 publications found

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]

REN Gene-Disease associations (from GenCC):

• familial juvenile hyperuricemic nephropathy type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• renal tubular dysgenesis of genetic origin

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REN	NM_000537.4	c.99-1347A>T		intron_variant	Intron 1 of 9	ENST00000272190.9	NP_000528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REN	ENST00000272190.9	c.99-1347A>T		intron_variant	Intron 1 of 9	1	NM_000537.4	ENSP00000272190.8
REN	ENST00000638118.1	c.-16-1347A>T		intron_variant	Intron 3 of 11	5		ENSP00000490307.1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48071 AN: 152008 Hom.: 8355 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.319

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.316 AC: 48133 AN: 152126 Hom.: 8370 Cov.: 32 AF XY: 0.311 AC XY: 23152 AN XY: 74390

African (AFR) AF: 0.479 AC: 19895 AN: 41496

American (AMR) AF: 0.280 AC: 4272 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3472

East Asian (EAS) AF: 0.181 AC: 938 AN: 5172

South Asian (SAS) AF: 0.262 AC: 1265 AN: 4822

European-Finnish (FIN) AF: 0.202 AC: 2136 AN: 10590

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17546 AN: 67988

Other (OTH) AF: 0.316 AC: 665 AN: 2106

Alfa AF: 0.269 Hom.: 3307

Bravo AF: 0.329

Asia WGS AF: 0.230 AC: 804 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.81
PhyloP100		0.015
Mutation Taster		=100/0	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: rs6693954; hg19: chr1-204132638;