chr17-63498093-A-ACT

Variant names:

• chr17-63498093-A-ACT
• rs4366
• NM_000789.4:c.*730_*731dupCT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000789.4(ACE):​c.*730_*731dupCT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.52 (20935 hom., cov: 0)
  • Exomes 𝑓: 0.41 (237 hom.)
• Consequence: ACE NM_000789.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.813
• Publications: 8 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 -10 ACMG points.

• BP6: Variant 17-63498093-A-ACT is Benign according to our data. Variant chr17-63498093-A-ACT is described in ClinVar as Benign. ClinVar VariationId is 324435.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.*730_*731dupCT		3_prime_UTR_variant	Exon 25 of 25	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.*730_*731dupCT		3_prime_UTR_variant	Exon 25 of 25	1	NM_000789.4	ENSP00000290866.4
ENSG00000264813	ENST00000577647.2	n.1969+1111_1969+1112dupCT		intron_variant	Intron 13 of 30	2		ENSP00000464149.1
ACE	ENST00000428043.5	c.*1073_*1074dupCT		3_prime_UTR_variant	Exon 24 of 24	2		ENSP00000397593.2

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79162 AN: 151808 Hom.: 20880 Cov.: 0

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.600

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.478

GnomAD4 exome AF: 0.407 AC: 951 AN: 2334 Hom.: 237 Cov.: 0 AF XY: 0.412 AC XY: 480 AN XY: 1164

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AF: 0.446 AC: 125 AN: 280

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 2 AN: 16

East Asian (EAS) AF: 0.438 AC: 7 AN: 16

South Asian (SAS) AF: 0.603 AC: 41 AN: 68

European-Finnish (FIN) AF: 0.262 AC: 11 AN: 42

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.396 AC: 708 AN: 1786

Other (OTH) AF: 0.467 AC: 56 AN: 120

GnomAD4 genome AF: 0.522 AC: 79281 AN: 151926 Hom.: 20935 Cov.: 0 AF XY: 0.523 AC XY: 38842 AN XY: 74242

African (AFR) AF: 0.599 AC: 24824 AN: 41432

American (AMR) AF: 0.558 AC: 8532 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1286 AN: 3472

East Asian (EAS) AF: 0.601 AC: 3083 AN: 5134

South Asian (SAS) AF: 0.618 AC: 2986 AN: 4828

European-Finnish (FIN) AF: 0.458 AC: 4826 AN: 10548

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.474 AC: 32223 AN: 67916

Other (OTH) AF: 0.483 AC: 1021 AN: 2112

Alfa AF: 0.273 Hom.: 510

Bravo AF: 0.523

Asia WGS AF: 0.663 AC: 2304 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal tubular dysgenesis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4366; hg19: chr17-61575454;