rs4317

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000290863.10(ACE):c.94T>C(p.Ser32Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00988 in 1,604,746 control chromosomes in the GnomAD database, including 1,164 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.051 ( 588 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 576 hom. )

Consequence

ACE
ENST00000290863.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.909

Publications

13 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.5672736E-4).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4 link	c.1922-275T>C		intron_variant	Intron 12 of 24	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000264813	ENST00000577647.2 link	n.94T>C		non_coding_transcript_exon_variant	Exon 1 of 31	2		ENSP00000464149.1
ACE	ENST00000290866.10 link	c.1922-275T>C		intron_variant	Intron 12 of 24	1	NM_000789.4	ENSP00000290866.4

Frequencies

GnomAD3 genomes

AF:

0.0506

AC:

7687

AN:

152056

Hom.:

582

Cov.:

show subpopulations

Gnomad AFR

AF:

0.174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0234

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.0364

GnomAD2 exomes

AF:

0.0128

AC:

2971

AN:

232990

AF XY:

0.00949

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.0100

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000485

Gnomad NFE exome

AF:

0.000619

Gnomad OTH exome

AF:

0.00887

GnomAD4 exome

AF:

0.00561

AC:

8147

AN:

1452572

Hom.:

576

Cov.:

AF XY:

0.00482

AC XY:

3477

AN XY:

721640

show subpopulations

African (AFR)

AF:

0.184

AC:

6141

AN:

33300

American (AMR)

AF:

0.0115

AC:

494

AN:

43094

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25960

East Asian (EAS)

AF:

0.00

AC:

AN:

39308

South Asian (SAS)

AF:

0.000520

AC:

AN:

84546

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52708

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000504

AC:

558

AN:

1107802

Other (OTH)

AF:

0.0140

AC:

839

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

487

973

1460

1946

2433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<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:

0.0507

AC:

7712

AN:

152174

Hom.:

588

Cov.:

AF XY:

0.0483

AC XY:

3590

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.174

AC:

7221

AN:

41494

American (AMR)

AF:

0.0233

AC:

357

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

68000

Other (OTH)

AF:

0.0360

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

343

686

1028

1371

1714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0135

Hom.:

393

Bravo

AF:

0.0587

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.154

AC:

660

ESP6500EA

AF:

0.000709

AC:

ExAC

AF:

0.0149

AC:

1807

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.4

(source)

DANN

Benign

0.40

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.21

T;T

MetaRNN

Benign

0.00086

T;T

MetaSVM

Benign

-0.99

PhyloP100

-0.91

PROVEAN

Benign

-0.93

N;N

REVEL

Benign

0.0070

Sift

Benign

0.22

T;T

Sift4G

Uncertain

0.019

D;D

Polyphen

0.0

B;.

Vest4

0.019

ClinPred

0.00036

GERP RS

-4.8

PromoterAI

0.050

Neutral

(source)

Mutation Taster

=96/4

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

Computational scores

Splicing

Publications

Other links and lift over