rs11571084

Variant names:

• chr1-204159704-C-T
• rs11571084
• NM_000537.4:c.493-109G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000537.4(REN):​c.493-109G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 921,392 control chromosomes in the GnomAD database, including 502 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 0.025 (72 hom., cov: 32)
  • Exomes 𝑓: 0.031 (430 hom.)
• Consequence: REN NM_000537.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.906
• Publications: 1 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=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.025 (3801/152268) while in subpopulation NFE AF = 0.037 (2515/68004). AF 95% confidence interval is 0.0358. There are 72 homozygotes in GnomAd4. There are 1832 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 72 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000537.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REN	NM_000537.4	MANE Select	c.493-109G>A		intron	N/A	NP_000528.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REN	ENST00000272190.9	TSL:1 MANE Select	c.493-109G>A		intron	N/A	ENSP00000272190.8
	REN	ENST00000638118.1	TSL:5	c.379-109G>A		intron	N/A	ENSP00000490307.1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3804 AN: 152150 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.00652

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0401

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0308 AC: 23727 AN: 769124 Hom.: 430 AF XY: 0.0307 AC XY: 12449 AN XY: 406090

African (AFR) AF: 0.00682 AC: 137 AN: 20076

American (AMR) AF: 0.0164 AC: 613 AN: 37284

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 832 AN: 21222

East Asian (EAS) AF: 0.0000575 AC: 2 AN: 34788

South Asian (SAS) AF: 0.0152 AC: 1044 AN: 68732

European-Finnish (FIN) AF: 0.0423 AC: 1904 AN: 45064

Middle Eastern (MID) AF: 0.0499 AC: 160 AN: 3208

European-Non Finnish (NFE) AF: 0.0357 AC: 17886 AN: 501260

Other (OTH) AF: 0.0306 AC: 1149 AN: 37490

GnomAD4 genome AF: 0.0250 AC: 3801 AN: 152268 Hom.: 72 Cov.: 32 AF XY: 0.0246 AC XY: 1832 AN XY: 74452

African (AFR) AF: 0.00650 AC: 270 AN: 41556

American (AMR) AF: 0.0209 AC: 319 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 140 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4830

European-Finnish (FIN) AF: 0.0401 AC: 426 AN: 10614

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0370 AC: 2515 AN: 68004

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.0357 Hom.: 51

Bravo AF: 0.0231

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.61
DANN	Benign	0.66
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism

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: rs11571084; hg19: chr1-204128832;