17-63477132-T-TGCTGCC

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP6_Very_Strong BA1

The NM_000789.4(ACE):c.50_55dup(p.Pro17_Leu18dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00598 in 1,420,308 control chromosomes in the GnomAD database, including 161 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (30 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (131 hom.)
• Consequence: ACE NM_000789.4 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0140

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 Benign. Variant got -14 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
• BP6: Variant 17-63477132-T-TGCTGCC is Benign according to our data. Variant chr17-63477132-T-TGCTGCC is described in ClinVar as [Likely_benign]. Clinvar id is 324358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACE	NM_000789.4	c.50_55dup	p.Pro17_Leu18dup	inframe_insertion	1/25	ENST00000290866.10
ACE	NM_001382700.1	c.-186_-181dup		5_prime_UTR_variant	1/22
ACE	NM_001382701.1	c.-565_-560dup		5_prime_UTR_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACE	ENST00000290866.10	c.50_55dup	p.Pro17_Leu18dup	inframe_insertion	1/25	1	NM_000789.4	P1

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1451 AN: 150972 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00771

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00353

Gnomad SAS AF: 0.0601

Gnomad FIN AF: 0.000193

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00916

GnomAD3 exomes AF: 0.0111 AC: 770 AN: 69620 Hom.: 23 AF XY: 0.0144 AC XY: 582 AN XY: 40330

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.00219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00155

Gnomad SAS exome AF: 0.0442

Gnomad FIN exome AF: 0.000222

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00553 AC: 7020 AN: 1269226 Hom.: 131 Cov.: 29 AF XY: 0.00658 AC XY: 4110 AN XY: 624786

Gnomad4 AFR exome AF: 0.0233

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00105

Gnomad4 SAS exome AF: 0.0466

Gnomad4 FIN exome AF: 0.000501

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00664

GnomAD4 genome AF: 0.00974 AC: 1471 AN: 151082 Hom.: 30 Cov.: 31 AF XY: 0.0105 AC XY: 772 AN XY: 73850

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00770

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00354

Gnomad4 SAS AF: 0.0597

Gnomad4 FIN AF: 0.000193

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.0186

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal tubular dysgenesis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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;