1-204159726-T-G

Variant names:

• chr1-204159726-T-G
• rs1464816
• NM_000537.4:c.493-131A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000537.4(REN):​c.493-131A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 759,204 control chromosomes in the GnomAD database, including 168,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.66 (33308 hom., cov: 31)
  • Exomes 𝑓: 0.67 (135500 hom.)
• Consequence: REN NM_000537.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0670
• Publications: 20 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-204159726-T-G is Benign according to our data. Variant chr1-204159726-T-G is described in ClinVar as Benign. ClinVar VariationId is 1249555.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REN	NM_000537.4	c.493-131A>C		intron_variant	Intron 4 of 9	ENST00000272190.9	NP_000528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REN	ENST00000272190.9	c.493-131A>C		intron_variant	Intron 4 of 9	1	NM_000537.4	ENSP00000272190.8
REN	ENST00000638118.1	c.379-131A>C		intron_variant	Intron 6 of 11	5		ENSP00000490307.1

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100474 AN: 151848 Hom.: 33274 Cov.: 31

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.679

GnomAD4 exome AF: 0.666 AC: 404416 AN: 607238 Hom.: 135500 AF XY: 0.670 AC XY: 218476 AN XY: 326094

African (AFR) AF: 0.660 AC: 11120 AN: 16860

American (AMR) AF: 0.711 AC: 24726 AN: 34788

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 12333 AN: 19608

East Asian (EAS) AF: 0.765 AC: 25000 AN: 32668

South Asian (SAS) AF: 0.740 AC: 46159 AN: 62362

European-Finnish (FIN) AF: 0.642 AC: 24121 AN: 37550

Middle Eastern (MID) AF: 0.739 AC: 1914 AN: 2590

European-Non Finnish (NFE) AF: 0.645 AC: 237617 AN: 368602

Other (OTH) AF: 0.665 AC: 21426 AN: 32210

GnomAD4 genome AF: 0.662 AC: 100562 AN: 151966 Hom.: 33308 Cov.: 31 AF XY: 0.664 AC XY: 49346 AN XY: 74268

African (AFR) AF: 0.657 AC: 27211 AN: 41442

American (AMR) AF: 0.709 AC: 10833 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2183 AN: 3470

East Asian (EAS) AF: 0.750 AC: 3851 AN: 5136

South Asian (SAS) AF: 0.732 AC: 3528 AN: 4820

European-Finnish (FIN) AF: 0.638 AC: 6733 AN: 10560

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.648 AC: 44033 AN: 67952

Other (OTH) AF: 0.680 AC: 1437 AN: 2112

Alfa AF: 0.646 Hom.: 29836

Bravo AF: 0.665

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.49
PhyloP100		-0.067
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: rs1464816; hg19: chr1-204128854;