rs397514691

Positions:

• chr1-204160648-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000272190.9(REN):​c.404C>A​(p.Ser135Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: REN ENST00000272190.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.41

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 1-204160648-G-T is Pathogenic according to our data. Variant chr1-204160648-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 50211.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-204160648-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REN	NM_000537.4	c.404C>A	p.Ser135Tyr	missense_variant	4/10	ENST00000272190.9	NP_000528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REN	ENST00000272190.9	c.404C>A	p.Ser135Tyr	missense_variant	4/10	1	NM_000537.4	ENSP00000272190	P1
REN	ENST00000638118.1	c.290C>A	p.Ser97Tyr	missense_variant	6/12	5		ENSP00000490307

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Renal tubular dysgenesis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.67	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.0	D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0060	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.88		Loss of disorder (P = 0.0488);.;
MVP		0.95
MPC		1.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514691; hg19: chr1-204129776;