1-204159709-A-T

Variant names:

• chr1-204159709-A-T
• rs11571116
• NM_000537.4:c.493-114T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000537.4(REN):​c.493-114T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000136 in 733,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: REN NM_000537.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 0 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• renal tubular dysgenesis of genetic origin

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REN	NM_000537.4	MANE Select	c.493-114T>A		intron	N/A	NP_000528.1	P00797-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REN	ENST00000272190.9	TSL:1 MANE Select	c.493-114T>A		intron	N/A	ENSP00000272190.8	P00797-1
	REN	ENST00000851325.1		c.493-114T>A		intron	N/A	ENSP00000521384.1
	REN	ENST00000638118.1	TSL:5	c.379-114T>A		intron	N/A	ENSP00000490307.1	A0A1B0GUZ2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000136 AC: 1 AN: 733666 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 388564

African (AFR) AF: 0.00 AC: 0 AN: 19290

American (AMR) AF: 0.00 AC: 0 AN: 36584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20938

East Asian (EAS) AF: 0.00 AC: 0 AN: 34278

South Asian (SAS) AF: 0.00 AC: 0 AN: 67440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3076

European-Non Finnish (NFE) AF: 0.00000212 AC: 1 AN: 472132

Other (OTH) AF: 0.00 AC: 0 AN: 36334

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.020
DANN	Benign	0.32
PhyloP100		-1.4

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: rs11571116; hg19: chr1-204128837;