rs4324

Positions:

• chr17-63485810-A-G
• chr17-63485810-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000789.4(ACE):​c.2058+438A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 243,108 control chromosomes in the GnomAD database, including 26,211 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (16109 hom., cov: 27)
  • Exomes 𝑓: 0.44 (10102 hom.)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.131

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACE	NM_000789.4	c.2058+438A>G		intron_variant		ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.2058+438A>G		intron_variant		1	NM_000789.4	ENSP00000290866	P1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 68691 AN: 149190 Hom.: 16080 Cov.: 27

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.416

GnomAD4 exome AF: 0.444 AC: 41666 AN: 93816 Hom.: 10102 Cov.: 0 AF XY: 0.449 AC XY: 22261 AN XY: 49600

Gnomad4 AFR exome AF: 0.352

Gnomad4 AMR exome AF: 0.524

Gnomad4 ASJ exome AF: 0.314

Gnomad4 EAS exome AF: 0.633

Gnomad4 SAS exome AF: 0.518

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.421

GnomAD4 genome AF: 0.461 AC: 68753 AN: 149292 Hom.: 16109 Cov.: 27 AF XY: 0.462 AC XY: 33478 AN XY: 72426

Gnomad4 AFR AF: 0.415

Gnomad4 AMR AF: 0.516

Gnomad4 ASJ AF: 0.369

Gnomad4 EAS AF: 0.661

Gnomad4 SAS AF: 0.593

Gnomad4 FIN AF: 0.431

Gnomad4 NFE AF: 0.463

Gnomad4 OTH AF: 0.423

Alfa AF: 0.464 Hom.: 2114

Bravo AF: 0.461

Asia WGS AF: 0.634 AC: 2205 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.2
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs4324; hg19: chr17-61563171;