rs4309

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000789.4(ACE):c.1215C>T(p.Pro405Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,613,878 control chromosomes in the GnomAD database, including 155,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 11850 hom., cov: 32)

Exomes 𝑓: 0.44 ( 143412 hom. )

Consequence

ACE
NM_000789.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.05

Publications

74 publications found

Variant links:

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

ACE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 17-63482562-C-T is Benign according to our data. Variant chr17-63482562-C-T is described in ClinVar as Benign. ClinVar VariationId is 256799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4 link	c.1215C>T	p.Pro405Pro	synonymous_variant	Exon 8 of 25	ENST00000290866.10	NP_000780.1	P12821-1B4DKH4
ACE	NM_001382700.1 link	c.648C>T	p.Pro216Pro	synonymous_variant	Exon 5 of 22		NP_001369629.1
ACE	NM_001382701.1 link	c.363C>T	p.Pro121Pro	synonymous_variant	Exon 6 of 23		NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10 link	c.1215C>T	p.Pro405Pro	synonymous_variant	Exon 8 of 25	1	NM_000789.4	ENSP00000290866.4		P12821-1

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56212

AN:

152006

Hom.:

11840

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.369

Gnomad AMR

AF:

0.497

Gnomad ASJ

AF:

0.357

Gnomad EAS

AF:

0.646

Gnomad SAS

AF:

0.537

Gnomad FIN

AF:

0.388

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.430

Gnomad OTH

AF:

0.363

GnomAD2 exomes

AF:

0.457

AC:

114893

AN:

251344

AF XY:

0.459

show subpopulations

Gnomad AFR exome

AF:

0.152

Gnomad AMR exome

AF:

0.598

Gnomad ASJ exome

AF:

0.352

Gnomad EAS exome

AF:

0.651

Gnomad FIN exome

AF:

0.384

Gnomad NFE exome

AF:

0.429

Gnomad OTH exome

AF:

0.439

GnomAD4 exome

AF:

0.437

AC:

638970

AN:

1461754

Hom.:

143412

Cov.:

AF XY:

0.439

AC XY:

319176

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.148

AC:

4964

AN:

33480

American (AMR)

AF:

0.586

AC:

26199

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.353

AC:

9237

AN:

26134

East Asian (EAS)

AF:

0.611

AC:

24268

AN:

39700

South Asian (SAS)

AF:

0.534

AC:

46042

AN:

86254

European-Finnish (FIN)

AF:

0.386

AC:

20576

AN:

53352

Middle Eastern (MID)

AF:

0.333

AC:

1918

AN:

5768

European-Non Finnish (NFE)

AF:

0.432

AC:

480173

AN:

1111962

Other (OTH)

AF:

0.424

AC:

25593

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

22392

44785

67177

89570

111962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14722

29444

44166

58888

73610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.370

AC:

56231

AN:

152124

Hom.:

11850

Cov.:

AF XY:

0.375

AC XY:

27902

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.167

AC:

6944

AN:

41520

American (AMR)

AF:

0.498

AC:

7619

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

1240

AN:

3470

East Asian (EAS)

AF:

0.647

AC:

3325

AN:

5142

South Asian (SAS)

AF:

0.539

AC:

2596

AN:

4820

European-Finnish (FIN)

AF:

0.388

AC:

4108

AN:

10590

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.430

AC:

29228

AN:

67974

Other (OTH)

AF:

0.360

AC:

758

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1711

3422

5132

6843

8554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

554

1108

1662

2216

2770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.411

Hom.:

49242

Bravo

AF:

0.363

Asia WGS

AF:

0.568

AC:

1974

AN:

3478

EpiCase

AF:

0.417

EpiControl

AF:

0.409

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Renal tubular dysgenesis

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.36

(source)

DANN

Benign

0.88

PhyloP100

-4.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over