17-63477132-TGCTGCC-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000789.4(ACE):βc.50_55delβ(p.Pro17_Leu18del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,420,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000046 ( 0 hom., cov: 31)
Exomes π: 0.000036 ( 0 hom. )
Consequence
ACE
NM_000789.4 inframe_deletion
NM_000789.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.20
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
In a signal_peptide (size 28) in uniprot entity ACE_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000789.4
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ACE | NM_000789.4 | c.50_55del | p.Pro17_Leu18del | inframe_deletion | 1/25 | ENST00000290866.10 | NP_000780.1 | |
| ACE | NM_001382700.1 | c.-186_-181del | 5_prime_UTR_variant | 1/22 | NP_001369629.1 | |||
| ACE | NM_001382701.1 | c.-565_-560del | 5_prime_UTR_variant | 1/23 | NP_001369630.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ACE | ENST00000290866.10 | c.50_55del | p.Pro17_Leu18del | inframe_deletion | 1/25 | 1 | NM_000789.4 | ENSP00000290866 | P1 |
Frequencies
GnomAD3 genomes 0.0000464 AC: 7AN: 150976Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000575 AC: 4AN: 69620Hom.: 0 AF XY: 0.0000744 AC XY: 3AN XY: 40330
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GnomAD4 exome AF: 0.0000362 AC: 46AN: 1269426Hom.: 0 AF XY: 0.0000480 AC XY: 30AN XY: 624926
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GnomAD4 genome 0.0000463 AC: 7AN: 151086Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3AN XY: 73854
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microvascular complications of diabetes, susceptibility to, 3;C3281105:Hemorrhage, intracerebral, susceptibility to;C5681536:Renal tubular dysgenesis of genetic origin Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 18, 2022 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 28, 2022 | 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with ACE-related conditions. This variant is present in population databases (rs767132000, gnomAD 0.04%). This variant, c.50_55del, results in the deletion of 2 amino acid(s) of the ACE protein (p.Pro17_Leu18del), but otherwise preserves the integrity of the reading frame. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at