17-63477132-TGCTGCC-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000789.4(ACE):c.50_55del(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ACE NM_000789.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a signal_peptide (size 28) in uniprot entity ACE_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_000789.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACE	NM_000789.4	c.50_55del	p.Pro17_Leu18del	inframe_deletion	1/25	ENST00000290866.10
ACE	NM_001382700.1	c.-186_-181del		5_prime_UTR_variant	1/22
ACE	NM_001382701.1	c.-565_-560del		5_prime_UTR_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACE	ENST00000290866.10	c.50_55del	p.Pro17_Leu18del	inframe_deletion	1/25	1	NM_000789.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000464 AC: 7 AN: 150976 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000785

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.0000575 AC: 4 AN: 69620 Hom.: 0 AF XY: 0.0000744 AC XY: 3 AN XY: 40330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000340

Gnomad EAS exome AF: 0.000389

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.0000362 AC: 46 AN: 1269426 Hom.: 0 AF XY: 0.0000480 AC XY: 30 AN XY: 624926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000283

Gnomad4 EAS exome AF: 0.000933

Gnomad4 SAS exome AF: 0.0000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000981

Gnomad4 OTH exome AF: 0.0000579

GnomAD4 genome AF: 0.0000463 AC: 7 AN: 151086 Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3 AN XY: 73854

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000787

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.000477

Bravo AF: 0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs532691783; hg19: chr17-61554493;