rs4980

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000789.4(ACE):c.3836G>A(p.Arg1279Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 1,557,882 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1279P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 26 hom. )

Consequence

ACE
NM_000789.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.24

Publications

26 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:

ENSG00000264813 (HGNC:):

ENSG00000264813 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066785812).

BP6

Variant 17-63497281-G-A is Benign according to our data. Variant chr17-63497281-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00528 (804/152260) while in subpopulation NFE AF = 0.007 (476/68004). AF 95% confidence interval is 0.00648. There are 0 homozygotes in GnomAd4. There are 393 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 26 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4 link	c.3836G>A	p.Arg1279Gln	missense_variant	Exon 25 of 25	ENST00000290866.10	NP_000780.1	P12821-1B4DKH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10 link	c.3836G>A	p.Arg1279Gln	missense_variant	Exon 25 of 25	1	NM_000789.4	ENSP00000290866.4		P12821-1
ENSG00000264813	ENST00000577647.2 link	n.1969+296G>A		intron_variant	Intron 13 of 30	2		ENSP00000464149.1		F6X3S4

Frequencies

GnomAD3 genomes

AF:

0.00528

AC:

803

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00725

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00700

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00410

AC:

635

AN:

154786

AF XY:

0.00404

show subpopulations

Gnomad AFR exome

AF:

0.00330

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.000603

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00559

Gnomad NFE exome

AF:

0.00658

Gnomad OTH exome

AF:

0.00691

GnomAD4 exome

AF:

0.00527

AC:

7406

AN:

1405622

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

3639

AN XY:

694598

show subpopulations

African (AFR)

AF:

0.00267

AC:

AN:

32230

American (AMR)

AF:

0.00272

AC:

100

AN:

36718

Ashkenazi Jewish (ASJ)

AF:

0.000753

AC:

AN:

25216

East Asian (EAS)

AF:

0.00

AC:

AN:

36860

South Asian (SAS)

AF:

0.00216

AC:

173

AN:

80138

European-Finnish (FIN)

AF:

0.00751

AC:

348

AN:

46322

Middle Eastern (MID)

AF:

0.00981

AC:

AN:

4690

European-Non Finnish (NFE)

AF:

0.00586

AC:

6354

AN:

1085198

Other (OTH)

AF:

0.00481

AC:

280

AN:

58250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

479

958

1438

1917

2396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<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:

0.00528

AC:

804

AN:

152260

Hom.:

Cov.:

AF XY:

0.00528

AC XY:

393

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00339

AC:

141

AN:

41552

American (AMR)

AF:

0.00484

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00725

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00700

AC:

476

AN:

68004

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00530

Hom.:

Bravo

AF:

0.00493

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00284

AC:

ESP6500EA

AF:

0.00541

AC:

ExAC

AF:

0.00312

AC:

352

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACE: BP4, BS2 -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Renal tubular dysgenesis

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.83

T;T;T

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;.;.

PhyloP100

2.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.051

Sift

Benign

0.083

T;T;T

Sift4G

Uncertain

0.019

D;D;D

Polyphen

0.016

B;B;.

Vest4

0.098

MVP

0.74

MPC

0.11

ClinPred

0.010

GERP RS

1.4

Varity_R

0.069

gMVP

0.45

Mutation Taster

=83/17

polymorphism

(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