chr1-204155017-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_000537.4(REN):c.1220G>T(p.Ter407Leuext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

REN
NM_000537.4 stop_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.127

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM4

Stoplost variant in NM_000537.4 Downstream stopcodon found after 60 codons.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REN	NM_000537.4 link	c.1220G>T	p.Ter407Leuext*?	stop_lost	Exon 10 of 10	ENST00000272190.9	NP_000528.1	P00797-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REN	ENST00000272190.9 link	c.1220G>T	p.Ter407Leuext*?	stop_lost	Exon 10 of 10	1	NM_000537.4	ENSP00000272190.8		P00797-1
REN	ENST00000638118.1 link	c.1106G>T	p.Ter369Leuext*?	stop_lost	Exon 12 of 12	5		ENSP00000490307.1		A0A1B0GUZ2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249642

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135060

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461484

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The REN p.*407Leuext*21 variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200760827) and in 5 of 281040 chromosomes at a frequency of 0.000018 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 5 of 24918 chromosomes (freq: 0.000201), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other or South Asian populations. The variant occurs outside of the splicing consensus sequence however 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the creation of a new 3' splice site. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Feb 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change disrupts the translational stop signal of the REN mRNA. It is expected to extend the length of the REN protein by 21 additional amino acid residues. This variant is present in population databases (rs200760827, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with REN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049731). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 22, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Normal stop codon changed to a Leu codon, leading to the addition of 21 amino acids at the C-terminus.; Has not been previously published as pathogenic or benign to our knowledge -

Familial juvenile hyperuricemic nephropathy type 2;C5681536:Renal tubular dysgenesis of genetic origin

Uncertain:1

Feb 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.57

CADD

Benign

9.8

DANN

Benign

0.72

Eigen

Uncertain

0.19

Eigen_PC

Benign

-0.053

FATHMM_MKL

Uncertain

0.85

Vest4

0.14

GERP RS

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over