dbSNP rs4343: ACE:p.Thr776Thr (chr17-63488670-G-A) – ACMG Classification: Benign (-21 pts)

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.2328G>A(p.Thr776Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 1,608,750 control chromosomes in the GnomAD database, including 207,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24843 hom., cov: 27)

Exomes 𝑓: 0.50 ( 182884 hom. )

Consequence

ACE
NM_000789.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.03

Publications

299 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 17-63488670-G-A is Benign according to our data. Variant chr17-63488670-G-A is described in ClinVar as Benign. ClinVar VariationId is 256803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.03 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACE	NM_000789.4	MANE Select	c.2328G>A	p.Thr776Thr	synonymous	Exon 16 of 25	NP_000780.1
ACE	NM_001382700.1		c.1761G>A	p.Thr587Thr	synonymous	Exon 13 of 22	NP_001369629.1
ACE	NM_001382701.1		c.1476G>A	p.Thr492Thr	synonymous	Exon 14 of 23	NP_001369630.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACE	ENST00000290866.10	TSL:1 MANE Select	c.2328G>A	p.Thr776Thr	synonymous	Exon 16 of 25	ENSP00000290866.4
ACE	ENST00000290863.10	TSL:1	c.606G>A	p.Thr202Thr	synonymous	Exon 5 of 14	ENSP00000290863.6
ENSG00000264813	ENST00000577647.2	TSL:2	n.606G>A		non_coding_transcript_exon	Exon 5 of 31	ENSP00000464149.1

Frequencies

GnomAD3 genomes

AF:

0.562

AC:

83465

AN:

148590

Hom.:

24775

Cov.:

show subpopulations

Gnomad AFR

AF:

0.751

Gnomad AMI

AF:

0.408

Gnomad AMR

AF:

0.571

Gnomad ASJ

AF:

0.378

Gnomad EAS

AF:

0.655

Gnomad SAS

AF:

0.594

Gnomad FIN

AF:

0.435

Gnomad MID

AF:

0.406

Gnomad NFE

AF:

0.469

Gnomad OTH

AF:

0.504

GnomAD2 exomes

AF:

0.533

AC:

134087

AN:

251352

AF XY:

0.526

show subpopulations

Gnomad AFR exome

AF:

0.760

Gnomad AMR exome

AF:

0.610

Gnomad ASJ exome

AF:

0.376

Gnomad EAS exome

AF:

0.670

Gnomad FIN exome

AF:

0.445

Gnomad NFE exome

AF:

0.472

Gnomad OTH exome

AF:

0.505

GnomAD4 exome

AF:

0.496

AC:

723840

AN:

1460046

Hom.:

182884

Cov.:

AF XY:

0.496

AC XY:

360156

AN XY:

726438

show subpopulations

African (AFR)

AF:

0.761

AC:

25480

AN:

33462

American (AMR)

AF:

0.605

AC:

27074

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.378

AC:

9861

AN:

26118

East Asian (EAS)

AF:

0.649

AC:

25763

AN:

39682

South Asian (SAS)

AF:

0.588

AC:

50686

AN:

86214

European-Finnish (FIN)

AF:

0.445

AC:

23744

AN:

53308

Middle Eastern (MID)

AF:

0.428

AC:

2470

AN:

5768

European-Non Finnish (NFE)

AF:

0.476

AC:

528098

AN:

1110458

Other (OTH)

AF:

0.508

AC:

30664

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

23314

46627

69941

93254

116568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15894

31788

47682

63576

79470

<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:

0.562

AC:

83595

AN:

148704

Hom.:

24843

Cov.:

AF XY:

0.560

AC XY:

40536

AN XY:

72338

show subpopulations

African (AFR)

AF:

0.752

AC:

30569

AN:

40658

American (AMR)

AF:

0.572

AC:

8418

AN:

14716

Ashkenazi Jewish (ASJ)

AF:

0.378

AC:

1301

AN:

3440

East Asian (EAS)

AF:

0.656

AC:

3197

AN:

4876

South Asian (SAS)

AF:

0.595

AC:

2746

AN:

4612

European-Finnish (FIN)

AF:

0.435

AC:

4395

AN:

10106

Middle Eastern (MID)

AF:

0.406

AC:

117

AN:

288

European-Non Finnish (NFE)

AF:

0.469

AC:

31432

AN:

67046

Other (OTH)

AF:

0.510

AC:

1056

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

1442

2885

4327

5770

7212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

696

1392

2088

2784

3480

<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:

0.505

Hom.:

85436

Bravo

AF:

0.580

EpiCase

AF:

0.461

EpiControl

AF:

0.445

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Renal tubular dysgenesis (2)

Myocardial infarction, susceptibility to (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.23

(source)

DANN

Benign

0.44

PhyloP100

-1.0

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over