17-63486097-A-G

Variant names:

• chr17-63486097-A-G
• rs4329
• NM_000789.4:c.2059-460A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000789.4(ACE):​c.2059-460A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 152,090 control chromosomes in the GnomAD database, including 16,612 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 (16612 hom., cov: 33)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.728
• Publications: 51 publications found

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]

ACE Gene-Disease associations (from GenCC):

• renal tubular dysgenesis of genetic origin

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intracerebral hemorrhage

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264813 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000789.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	NM_000789.4	MANE Select	c.2059-460A>G		intron	N/A	NP_000780.1
	ACE	NM_001382700.1		c.1492-460A>G		intron	N/A	NP_001369629.1
	ACE	NM_001382701.1		c.1207-460A>G		intron	N/A	NP_001369630.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	ENST00000290866.10	TSL:1 MANE Select	c.2059-460A>G		intron	N/A	ENSP00000290866.4
	ACE	ENST00000290863.10	TSL:1	c.337-460A>G		intron	N/A	ENSP00000290863.6
	ENSG00000264813	ENST00000577647.2	TSL:2	n.337-460A>G		intron	N/A	ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70438 AN: 151972 Hom.: 16583 Cov.: 33

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.419

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.464 AC: 70503 AN: 152090 Hom.: 16612 Cov.: 33 AF XY: 0.466 AC XY: 34655 AN XY: 74336

African (AFR) AF: 0.418 AC: 17323 AN: 41470

American (AMR) AF: 0.522 AC: 7974 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1277 AN: 3470

East Asian (EAS) AF: 0.663 AC: 3432 AN: 5176

South Asian (SAS) AF: 0.595 AC: 2861 AN: 4812

European-Finnish (FIN) AF: 0.447 AC: 4731 AN: 10576

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31533 AN: 67980

Other (OTH) AF: 0.426 AC: 900 AN: 2114

Alfa AF: 0.463 Hom.: 75877

Bravo AF: 0.462

Asia WGS AF: 0.636 AC: 2210 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.41
DANN	Benign	0.39
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4329; hg19: chr17-61563458;