rs797045079

chr17-63477105-CCTCGGGCCGCCGGGGGCCGG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000789.4(ACE):c.12_31del(p.Ser5AlafsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000304 in 1,317,378 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: ACE NM_000789.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.999

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 50 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-63477105-CCTCGGGCCGCCGGGGGCCGG-C is Pathogenic according to our data. Variant chr17-63477105-CCTCGGGCCGCCGGGGGCCGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACE	NM_000789.4	c.12_31del	p.Ser5AlafsTer31	frameshift_variant	1/25	ENST00000290866.10
ACE	NM_001382700.1	c.-224_-205del		5_prime_UTR_variant	1/22
ACE	NM_001382701.1	c.-603_-584del		5_prime_UTR_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACE	ENST00000290866.10	c.12_31del	p.Ser5AlafsTer31	frameshift_variant	1/25	1	NM_000789.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151282 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.58e-7 AC: 1 AN: 1165988 Hom.: 0 AF XY: 0.00000176 AC XY: 1 AN XY: 566678

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000103

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151390 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74000

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal tubular dysgenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 24, 2014

The Ser5AlafsX31 variant in ACE has not been previously reported in individuals with renal tubular dysgenesis and data from large population studies is insufficient to assess the frequency of this variant. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 5 and lead to a premature termination codon 31 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function variants in exon 1 of the ACE gene - encoding the signal peptide - have been associated with renal tubular dysgenesis in homozygous and compound heterozygous individuals (Gribouval 2012). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2018

The c.12_31del20 variant in the ACE gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.12_31del20 variant causes a frameshift starting with codon Serine 5, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 31 of the new reading frame, denoted p.Ser5AlafsX31. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.12_31del20 variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.12_31del20 as a likely pathogenic variant. -

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: rs797045079; hg19: chr17-61554466;