1-204156859-T-C

Variant names:

• chr1-204156859-T-C
• rs3730103
• NM_000537.4:c.699-63A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000537.4(REN):​c.699-63A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0687 in 1,603,728 control chromosomes in the GnomAD database, including 6,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1974 hom., cov: 32)
  • Exomes 𝑓: 0.064 (4085 hom.)
• Consequence: REN NM_000537.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.337
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-204156859-T-C is Benign according to our data. Variant chr1-204156859-T-C is described in ClinVar as Benign. ClinVar VariationId is 1247423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REN	NM_000537.4	c.699-63A>G		intron_variant	Intron 6 of 9	ENST00000272190.9	NP_000528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REN	ENST00000272190.9	c.699-63A>G		intron_variant	Intron 6 of 9	1	NM_000537.4	ENSP00000272190.8
REN	ENST00000638118.1	c.585-63A>G		intron_variant	Intron 8 of 11	5		ENSP00000490307.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17994 AN: 151954 Hom.: 1971 Cov.: 32

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0396

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.0635 AC: 92187 AN: 1451656 Hom.: 4085 AF XY: 0.0624 AC XY: 45081 AN XY: 722704

African (AFR) AF: 0.300 AC: 10032 AN: 33408

American (AMR) AF: 0.0504 AC: 2255 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0281 AC: 734 AN: 26114

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39682

South Asian (SAS) AF: 0.0448 AC: 3860 AN: 86084

European-Finnish (FIN) AF: 0.0540 AC: 2540 AN: 47032

Middle Eastern (MID) AF: 0.0782 AC: 420 AN: 5370

European-Non Finnish (NFE) AF: 0.0615 AC: 68245 AN: 1109052

Other (OTH) AF: 0.0679 AC: 4090 AN: 60196

GnomAD4 genome AF: 0.119 AC: 18026 AN: 152072 Hom.: 1974 Cov.: 32 AF XY: 0.115 AC XY: 8540 AN XY: 74370

African (AFR) AF: 0.290 AC: 11995 AN: 41422

American (AMR) AF: 0.0735 AC: 1124 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 105 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.0396 AC: 191 AN: 4818

European-Finnish (FIN) AF: 0.0503 AC: 533 AN: 10588

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0561 AC: 3814 AN: 68004

Other (OTH) AF: 0.104 AC: 220 AN: 2108

Alfa AF: 0.0676 Hom.: 286

Bravo AF: 0.128

Asia WGS AF: 0.0290 AC: 103 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 2021

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	-0.89
CADD	Benign	6.2
DANN	Benign	0.44
PhyloP100		-0.34
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: rs3730103; hg19: chr1-204125987;