rs4354

Positions:

• chr17-63494091-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000789.4(ACE):​c.3281+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 1,612,888 control chromosomes in the GnomAD database, including 1,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (557 hom., cov: 32)
  • Exomes 𝑓: 0.026 (908 hom.)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.38

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 17-63494091-C-T is Benign according to our data. Variant chr17-63494091-C-T is described in ClinVar as [Benign]. Clinvar id is 1235934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACE	NM_000789.4	c.3281+25C>T		intron_variant		ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.3281+25C>T		intron_variant		1	NM_000789.4	ENSP00000290866	P1

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 8892 AN: 151972 Hom.: 553 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0396

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0565

GnomAD3 exomes AF: 0.0289 AC: 7231 AN: 249982 Hom.: 263 AF XY: 0.0277 AC XY: 3741 AN XY: 135140

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.00158

Gnomad SAS exome AF: 0.0285

Gnomad FIN exome AF: 0.00995

Gnomad NFE exome AF: 0.0229

Gnomad OTH exome AF: 0.0321

GnomAD4 exome AF: 0.0259 AC: 37847 AN: 1460798 Hom.: 908 Cov.: 32 AF XY: 0.0257 AC XY: 18703 AN XY: 726682

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.0272

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0346

GnomAD4 genome AF: 0.0587 AC: 8921 AN: 152090 Hom.: 557 Cov.: 32 AF XY: 0.0571 AC XY: 4246 AN XY: 74320

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.0395

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.00291

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0559

Alfa AF: 0.0373 Hom.: 43

Bravo AF: 0.0645

Asia WGS AF: 0.0330 AC: 115 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.12
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4354; hg19: chr17-61571452;