NM_000789.4:c.1922-44G>A

Variant names:

• chr17-63485192-G-A
• rs4320
• NM_000789.4:c.1922-44G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000789.4(ACE):​c.1922-44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 1,612,346 control chromosomes in the GnomAD database, including 185,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16219 hom., cov: 31)
  • Exomes 𝑓: 0.48 (168880 hom.)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.237
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-63485192-G-A is Benign according to our data. Variant chr17-63485192-G-A is described in ClinVar as Benign. ClinVar VariationId is 1273658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.648 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.1922-44G>A		intron	N/A	NP_000780.1
	ACE	NM_001382700.1		c.1355-44G>A		intron	N/A	NP_001369629.1
	ACE	NM_001382701.1		c.1070-44G>A		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.1922-44G>A		intron	N/A	ENSP00000290866.4
	ACE	ENST00000290863.10	TSL:1	c.200-44G>A		intron	N/A	ENSP00000290863.6
	ENSG00000264813	ENST00000577647.2	TSL:2	n.200-44G>A		intron	N/A	ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69518 AN: 151814 Hom.: 16191 Cov.: 31

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.416

GnomAD2 exomes AF: 0.500 AC: 123931 AN: 247918 AF XY: 0.499

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.580

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.671

Gnomad FIN exome AF: 0.445

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.475

GnomAD4 exome AF: 0.478 AC: 698074 AN: 1460414 Hom.: 168880 Cov.: 46 AF XY: 0.479 AC XY: 348108 AN XY: 726358

African (AFR) AF: 0.392 AC: 13123 AN: 33474

American (AMR) AF: 0.573 AC: 25479 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 9722 AN: 26110

East Asian (EAS) AF: 0.650 AC: 25781 AN: 39676

South Asian (SAS) AF: 0.579 AC: 49896 AN: 86136

European-Finnish (FIN) AF: 0.448 AC: 23768 AN: 53100

Middle Eastern (MID) AF: 0.365 AC: 2101 AN: 5764

European-Non Finnish (NFE) AF: 0.468 AC: 519892 AN: 1111300

Other (OTH) AF: 0.469 AC: 28312 AN: 60354

GnomAD4 genome AF: 0.458 AC: 69581 AN: 151932 Hom.: 16219 Cov.: 31 AF XY: 0.461 AC XY: 34251 AN XY: 74258

African (AFR) AF: 0.400 AC: 16564 AN: 41426

American (AMR) AF: 0.518 AC: 7916 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1302 AN: 3468

East Asian (EAS) AF: 0.667 AC: 3426 AN: 5140

South Asian (SAS) AF: 0.594 AC: 2855 AN: 4810

European-Finnish (FIN) AF: 0.449 AC: 4743 AN: 10574

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

European-Non Finnish (NFE) AF: 0.462 AC: 31415 AN: 67928

Other (OTH) AF: 0.422 AC: 889 AN: 2106

Alfa AF: 0.444 Hom.: 6212

Bravo AF: 0.455

Asia WGS AF: 0.636 AC: 2210 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.4
DANN	Benign	0.76
PhyloP100		-0.24
PromoterAI		0.0079	Neutral
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: rs4320; hg19: chr17-61562553;