17-63477128-CTGCTGCTGCCGCTGCCGCTGCTGT-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000789.4(ACE):c.47_70del(p.Leu16_Pro23del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,409,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: ACE NM_000789.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• 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 5 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
• PP5: Variant 17-63477128-CTGCTGCTGCCGCTGCCGCTGCTGT-C is Pathogenic according to our data. Variant chr17-63477128-CTGCTGCTGCCGCTGCCGCTGCTGT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1219086.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1}. Variant chr17-63477128-CTGCTGCTGCCGCTGCCGCTGCTGT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACE	NM_000789.4	c.47_70del	p.Leu16_Pro23del	inframe_deletion	1/25	ENST00000290866.10
ACE	NM_001382700.1	c.-189_-166del		5_prime_UTR_variant	1/22
ACE	NM_001382701.1	c.-568_-545del		5_prime_UTR_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACE	ENST00000290866.10	c.47_70del	p.Leu16_Pro23del	inframe_deletion	1/25	1	NM_000789.4	P1

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 31 AN: 151230 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000724

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: 0.000266

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000127 AC: 8 AN: 62808 Hom.: 0 AF XY: 0.000110 AC XY: 4 AN XY: 36344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000385

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000253 AC: 318 AN: 1257988 Hom.: 0 AF XY: 0.000225 AC XY: 139 AN XY: 618570

Gnomad4 AFR exome AF: 0.0000785

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000490

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.000565

GnomAD4 genome AF: 0.000205 AC: 31 AN: 151230 Hom.: 0 Cov.: 31 AF XY: 0.000217 AC XY: 16 AN XY: 73844

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.000724

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000266

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.000174

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 11, 2023	This variant, c.47_70del, results in the deletion of 8 amino acid(s) of the ACE protein (p.Leu16_Pro23del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.04%). This variant has been observed in individuals with renal tubular dysgenesis (PMID: 22095942). ClinVar contains an entry for this variant (Variation ID: 1219086). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2021	In-frame deletion of 8 amino acids in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22095942) -

Microvascular complications of diabetes, susceptibility to, 3;C3281105:Hemorrhage, intracerebral, susceptibility to;C5681536:Renal tubular dysgenesis of genetic origin Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 03, 2021

- -

Renal tubular dysgenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This 24 base pair in-frame deletion variant found in exon 1 of 25 leads to the loss of 8 amino acid residues. This variant has been previously reported in the homozygous state in two individuals and the compound heterozygous state with a pathogenic truncating variant in one individual with Renal Tubular Dysgenesis (PMID: 22095942). These individuals exhibited high renin expression, indicating a loss of ACE protein function. Variants in exon 1 of the ACE gene that completely disrupt the signal peptide sequence or result in the deletion of one or several leucine residues are predicted to prevent the normal translocation of the protein to the endoplasmic reticulum (PMID: 22095942, 19664745). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0096% (9/93296) and thus is presumed to be rare. Based on the available evidence, the c.47_70del (p.Leu16_Pro23del) variant is classified as Pathogenic. -

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: rs983649759; hg19: chr17-61554489;