chr1-204155961-G-A

Variant names:

• chr1-204155961-G-A
• rs3795575
• NM_000537.4:c.961-43C>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.961-43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,542,266 control chromosomes in the GnomAD database, including 14,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1585 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12454 hom.)
• Consequence: REN NM_000537.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.267
• Publications: 18 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=-0.93).
• BP6: Variant 1-204155961-G-A is Benign according to our data. Variant chr1-204155961-G-A is described in CliVar as Benign. Clinvar id is 1236555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-204155961-G-A is described in CliVar as Benign. Clinvar id is 1236555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-204155961-G-A is described in CliVar as Benign. Clinvar id is 1236555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-204155961-G-A is described in CliVar as Benign. Clinvar id is 1236555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-204155961-G-A is described in CliVar as Benign. Clinvar id is 1236555.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.961-43C>T		intron_variant	Intron 8 of 9	ENST00000272190.9	NP_000528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REN	ENST00000272190.9	c.961-43C>T		intron_variant	Intron 8 of 9	1	NM_000537.4	ENSP00000272190.8
REN	ENST00000638118.1	c.847-43C>T		intron_variant	Intron 10 of 11	5		ENSP00000490307.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21918 AN: 152030 Hom.: 1581 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0776

Gnomad SAS AF: 0.0944

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.137

GnomAD2 exomes AF: 0.139 AC: 34228 AN: 246470 AF XY: 0.136

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.0732

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.131 AC: 181683 AN: 1390118 Hom.: 12454 Cov.: 22 AF XY: 0.130 AC XY: 90594 AN XY: 695782

African (AFR) AF: 0.170 AC: 5431 AN: 31938

American (AMR) AF: 0.197 AC: 8746 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 4692 AN: 25652

East Asian (EAS) AF: 0.0859 AC: 3379 AN: 39346

South Asian (SAS) AF: 0.101 AC: 8585 AN: 84858

European-Finnish (FIN) AF: 0.142 AC: 7360 AN: 51856

Middle Eastern (MID) AF: 0.180 AC: 954 AN: 5294

European-Non Finnish (NFE) AF: 0.128 AC: 134751 AN: 1048794

Other (OTH) AF: 0.134 AC: 7785 AN: 57944

GnomAD4 genome AF: 0.144 AC: 21933 AN: 152148 Hom.: 1585 Cov.: 32 AF XY: 0.143 AC XY: 10663 AN XY: 74394

African (AFR) AF: 0.164 AC: 6821 AN: 41506

American (AMR) AF: 0.168 AC: 2563 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 660 AN: 3470

East Asian (EAS) AF: 0.0774 AC: 400 AN: 5168

South Asian (SAS) AF: 0.0944 AC: 455 AN: 4818

European-Finnish (FIN) AF: 0.141 AC: 1493 AN: 10594

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.134 AC: 9079 AN: 67994

Other (OTH) AF: 0.135 AC: 285 AN: 2112

Alfa AF: 0.134 Hom.: 1792

Bravo AF: 0.150

Asia WGS AF: 0.100 AC: 352 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	-0.93
CADD	Benign	1.2
DANN	Benign	0.58
PhyloP100		-0.27
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: rs3795575; hg19: chr1-204125089; COSMIC: COSV107237462; COSMIC: COSV107237462;