1-204157250-G-A

Variant names:

• chr1-204157250-G-A
• rs3730102
• NM_000537.4:c.698+111C>T

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.698+111C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,407,184 control chromosomes in the GnomAD database, including 13,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1552 hom., cov: 32)
  • Exomes 𝑓: 0.13 (11451 hom.)
• Consequence: REN NM_000537.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.529
• 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=-0.94).
• BP6: Variant 1-204157250-G-A is Benign according to our data. Variant chr1-204157250-G-A is described in ClinVar as Benign. ClinVar VariationId is 1281962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REN	NM_000537.4	c.698+111C>T		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.698+111C>T		intron_variant	Intron 6 of 9	1	NM_000537.4	ENSP00000272190.8
REN	ENST00000638118.1	c.584+111C>T		intron_variant	Intron 8 of 11	5		ENSP00000490307.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21692 AN: 152100 Hom.: 1549 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0780

Gnomad SAS AF: 0.0957

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.137

GnomAD4 exome AF: 0.132 AC: 165032 AN: 1254966 Hom.: 11451 AF XY: 0.131 AC XY: 83045 AN XY: 634980

African (AFR) AF: 0.164 AC: 4830 AN: 29462

American (AMR) AF: 0.198 AC: 8806 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 4556 AN: 24834

East Asian (EAS) AF: 0.0863 AC: 3339 AN: 38712

South Asian (SAS) AF: 0.102 AC: 8367 AN: 82158

European-Finnish (FIN) AF: 0.142 AC: 7586 AN: 53296

Middle Eastern (MID) AF: 0.180 AC: 920 AN: 5116

European-Non Finnish (NFE) AF: 0.129 AC: 119482 AN: 923544

Other (OTH) AF: 0.134 AC: 7146 AN: 53416

GnomAD4 genome AF: 0.143 AC: 21704 AN: 152218 Hom.: 1552 Cov.: 32 AF XY: 0.142 AC XY: 10582 AN XY: 74438

African (AFR) AF: 0.159 AC: 6591 AN: 41532

American (AMR) AF: 0.167 AC: 2555 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 658 AN: 3472

East Asian (EAS) AF: 0.0778 AC: 403 AN: 5178

South Asian (SAS) AF: 0.0956 AC: 461 AN: 4822

European-Finnish (FIN) AF: 0.141 AC: 1498 AN: 10604

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9074 AN: 68004

Other (OTH) AF: 0.135 AC: 286 AN: 2116

Alfa AF: 0.140 Hom.: 548

Bravo AF: 0.148

Asia WGS AF: 0.0990 AC: 346 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	-0.94
CADD	Benign	0.016
DANN	Benign	0.82
PhyloP100		-0.53
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: rs3730102; hg19: chr1-204126378; COSMIC: COSV65817768;