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rs4343

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000789.4(ACE):c.2328G>A(p.Thr776=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 1,608,750 control chromosomes in the GnomAD database, including 207,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24843 hom., cov: 27)
Exomes 𝑓: 0.50 ( 182884 hom. )

Consequence

ACE
NM_000789.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.03
Variant links:
Genes affected
ACE (HGNC:2707): (angiotensin I converting enzyme) This gene encodes an enzyme involved in blood pressure regulation and electrolyte balance. It catalyzes the conversion of angiotensin I into a physiologically active peptide angiotensin II. Angiotensin II is a potent vasopressor and aldosterone-stimulating peptide that controls blood pressure and fluid-electrolyte balance. This angiotensin converting enzyme (ACE) also inactivates the vasodilator protein, bradykinin. Accordingly, the encoded enzyme increases blood pressure and is a drug target of ACE inhibitors, which are often prescribed to reduce blood pressure. This enzyme additionally plays a role in fertility through its ability to cleave and release GPI-anchored membrane proteins in spermatozoa. Many studies have associated the presence or absence of a 287 bp Alu repeat element in this gene with the levels of circulating enzyme. This polymorphism, as well as mutations in this gene, have been implicated in a wide variety of diseases including cardiovascular pathophysiologies, psoriasis, renal disease, stroke, and Alzheimer's disease. Regulation of the homologous ACE2 gene may be involved in progression of disease caused by several human coronaviruses, including SARS-CoV and SARS-CoV-2. Alternative splicing results in multiple transcript variants encoding both somatic (sACE) and male-specific testicular (tACE) isoforms. [provided by RefSeq, Sep 2020]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 17-63488670-G-A is Benign according to our data. Variant chr17-63488670-G-A is described in ClinVar as [Benign]. Clinvar id is 256803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63488670-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.03 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACENM_000789.4 linkuse as main transcriptc.2328G>A p.Thr776= synonymous_variant 16/25 ENST00000290866.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACEENST00000290866.10 linkuse as main transcriptc.2328G>A p.Thr776= synonymous_variant 16/251 NM_000789.4 P1P12821-1

Frequencies

GnomAD3 genomes
AF:
0.562
AC:
83465
AN:
148590
Hom.:
24775
Cov.:
27
show subpopulations
Gnomad AFR
AF:
0.751
Gnomad AMI
AF:
0.408
Gnomad AMR
AF:
0.571
Gnomad ASJ
AF:
0.378
Gnomad EAS
AF:
0.655
Gnomad SAS
AF:
0.594
Gnomad FIN
AF:
0.435
Gnomad MID
AF:
0.406
Gnomad NFE
AF:
0.469
Gnomad OTH
AF:
0.504
GnomAD3 exomes
AF:
0.533
AC:
134087
AN:
251352
Hom.:
37221
AF XY:
0.526
AC XY:
71419
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.760
Gnomad AMR exome
AF:
0.610
Gnomad ASJ exome
AF:
0.376
Gnomad EAS exome
AF:
0.670
Gnomad SAS exome
AF:
0.592
Gnomad FIN exome
AF:
0.445
Gnomad NFE exome
AF:
0.472
Gnomad OTH exome
AF:
0.505
GnomAD4 exome
AF:
0.496
AC:
723840
AN:
1460046
Hom.:
182884
Cov.:
51
AF XY:
0.496
AC XY:
360156
AN XY:
726438
show subpopulations
Gnomad4 AFR exome
AF:
0.761
Gnomad4 AMR exome
AF:
0.605
Gnomad4 ASJ exome
AF:
0.378
Gnomad4 EAS exome
AF:
0.649
Gnomad4 SAS exome
AF:
0.588
Gnomad4 FIN exome
AF:
0.445
Gnomad4 NFE exome
AF:
0.476
Gnomad4 OTH exome
AF:
0.508
GnomAD4 genome
AF:
0.562
AC:
83595
AN:
148704
Hom.:
24843
Cov.:
27
AF XY:
0.560
AC XY:
40536
AN XY:
72338
show subpopulations
Gnomad4 AFR
AF:
0.752
Gnomad4 AMR
AF:
0.572
Gnomad4 ASJ
AF:
0.378
Gnomad4 EAS
AF:
0.656
Gnomad4 SAS
AF:
0.595
Gnomad4 FIN
AF:
0.435
Gnomad4 NFE
AF:
0.469
Gnomad4 OTH
AF:
0.510
Alfa
AF:
0.487
Hom.:
38374
Bravo
AF:
0.580
EpiCase
AF:
0.461
EpiControl
AF:
0.445

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Renal tubular dysgenesis Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxNov 10, 2018- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Myocardial infarction, susceptibility to Benign:1
Benign, no assertion criteria providedreference populationiDNA GenomicsOct 11, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
Cadd
Benign
0.23
Dann
Benign
0.44

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.

Other links and lift over

dbSNP: rs4343; hg19: chr17-61566031; COSMIC: COSV52007462; COSMIC: COSV52007462; API