17-63486691-A-G

Variant names:

• chr17-63486691-A-G
• rs4331
• NM_000789.4:c.2193A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000789.4(ACE):​c.2193A>G​(p.Ala731Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,613,954 control chromosomes in the GnomAD database, including 186,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16596 hom., cov: 34)
  • Exomes 𝑓: 0.48 (170182 hom.)
• Consequence: ACE NM_000789.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.30
• Publications: 63 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 - ACE

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• renal tubular dysgenesis of genetic origin

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

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264813 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-63486691-A-G is Benign according to our data. Variant chr17-63486691-A-G is described in ClinVar as Benign. ClinVar VariationId is 256800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.3 with no splicing effect.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	NM_000789.4	MANE Select	c.2193A>G	p.Ala731Ala	synonymous	Exon 14 of 25	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.1626A>G	p.Ala542Ala	synonymous	Exon 11 of 22	NP_001369629.1
	ACE	NM_001382701.1		c.1341A>G	p.Ala447Ala	synonymous	Exon 12 of 23	NP_001369630.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	ENST00000290866.10	TSL:1 MANE Select	c.2193A>G	p.Ala731Ala	synonymous	Exon 14 of 25	ENSP00000290866.4	P12821-1
	ACE	ENST00000290863.10	TSL:1	c.471A>G	p.Ala157Ala	synonymous	Exon 3 of 14	ENSP00000290863.6	P12821-3
	ENSG00000264813	ENST00000577647.2	TSL:2	n.471A>G		non_coding_transcript_exon	Exon 3 of 31	ENSP00000464149.1	F6X3S4

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70410 AN: 152074 Hom.: 16565 Cov.: 34

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.419

GnomAD2 exomes AF: 0.501 AC: 125883 AN: 251224 AF XY: 0.500

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.669

Gnomad FIN exome AF: 0.443

Gnomad NFE exome AF: 0.464

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.480 AC: 700987 AN: 1461760 Hom.: 170182 Cov.: 65 AF XY: 0.481 AC XY: 349574 AN XY: 727178

African (AFR) AF: 0.409 AC: 13708 AN: 33478

American (AMR) AF: 0.574 AC: 25683 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9518 AN: 26134

East Asian (EAS) AF: 0.649 AC: 25755 AN: 39696

South Asian (SAS) AF: 0.580 AC: 50047 AN: 86256

European-Finnish (FIN) AF: 0.445 AC: 23744 AN: 53386

Middle Eastern (MID) AF: 0.362 AC: 2089 AN: 5766

European-Non Finnish (NFE) AF: 0.469 AC: 521994 AN: 1111928

Other (OTH) AF: 0.471 AC: 28449 AN: 60394

GnomAD4 genome AF: 0.463 AC: 70481 AN: 152194 Hom.: 16596 Cov.: 34 AF XY: 0.466 AC XY: 34670 AN XY: 74424

African (AFR) AF: 0.416 AC: 17281 AN: 41528

American (AMR) AF: 0.522 AC: 7986 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1274 AN: 3470

East Asian (EAS) AF: 0.663 AC: 3430 AN: 5170

South Asian (SAS) AF: 0.595 AC: 2868 AN: 4822

European-Finnish (FIN) AF: 0.446 AC: 4729 AN: 10592

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

European-Non Finnish (NFE) AF: 0.464 AC: 31541 AN: 67992

Other (OTH) AF: 0.426 AC: 898 AN: 2110

Alfa AF: 0.462 Hom.: 70212

Bravo AF: 0.461

Asia WGS AF: 0.636 AC: 2212 AN: 3478

EpiCase AF: 0.450

EpiControl AF: 0.435

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Renal tubular dysgenesis (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.22
DANN	Benign	0.42
PhyloP100		-2.3
PromoterAI		-0.0042	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4331; hg19: chr17-61564052; COSMIC: COSV52003560; COSMIC: COSV52003560;