chr1-204155090-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000537.4(REN):​c.1147G>A​(p.Ala383Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

REN
NM_000537.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.79

Publications

0 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RENNM_000537.4 linkc.1147G>A p.Ala383Thr missense_variant Exon 10 of 10 ENST00000272190.9 NP_000528.1 P00797-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RENENST00000272190.9 linkc.1147G>A p.Ala383Thr missense_variant Exon 10 of 10 1 NM_000537.4 ENSP00000272190.8 P00797-1
RENENST00000638118.1 linkc.1033G>A p.Ala345Thr missense_variant Exon 12 of 12 5 ENSP00000490307.1 A0A1B0GUZ2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152246
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000802
AC:
2
AN:
249222
AF XY:
0.0000148
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000897
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461860
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727230
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53404
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111994
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152246
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74380
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41460
American (AMR)
AF:
0.0000654
AC:
1
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5204
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jul 02, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1147G>A (p.A383T) alteration is located in exon 10 (coding exon 10) of the REN gene. This alteration results from a G to A substitution at nucleotide position 1147, causing the alanine (A) at amino acid position 383 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.099
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.29
T;T
Eigen
Benign
0.18
Eigen_PC
Benign
0.22
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.80
T;T
M_CAP
Benign
0.030
D
MetaRNN
Uncertain
0.63
D;D
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
1.5
L;.
PhyloP100
5.8
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.98
N;.
REVEL
Benign
0.26
Sift
Benign
0.072
T;.
Sift4G
Benign
0.14
T;.
Polyphen
0.83
P;.
Vest4
0.14
MutPred
0.66
Gain of ubiquitination at K388 (P = 0.095);.;
MVP
0.72
MPC
0.54
ClinPred
0.92
D
GERP RS
3.0
Varity_R
0.60
gMVP
0.83
Mutation Taster
=52/48
polymorphism

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

Other links and lift over

dbSNP: rs1304427544; hg19: chr1-204124218; API