rs4343

Positions:

chr17-63488670-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000789.4(ACE):c.2328G>A(p.Thr776=) 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 256803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63488670-G-A is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACE	NM_000789.4 linkuse as main transcript	c.2328G>A	p.Thr776=	synonymous_variant	16/25	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10 linkuse as main transcript	c.2328G>A	p.Thr776=	synonymous_variant	16/25	1	NM_000789.4	ENSP00000290866	P1	P12821-1

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

GnomAD3 exomes

AF:

0.533

AC:

134087

AN:

251352

Hom.:

37221

AF XY:

0.526

AC XY:

71419

AN XY:

135848

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 SAS exome

AF:

0.592

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

Gnomad4 AFR exome

AF:

0.761

Gnomad4 AMR exome

AF:

0.605

Gnomad4 ASJ exome

AF:

0.378

Gnomad4 EAS exome

AF:

0.649

Gnomad4 SAS exome

AF:

0.588

Gnomad4 FIN exome

AF:

0.445

Gnomad4 NFE exome

AF:

0.476

Gnomad4 OTH exome

AF:

0.508

GnomAD4 genome

AF:

0.562

AC:

83595

AN:

148704

Hom.:

24843

Cov.:

AF XY:

0.560

AC XY:

40536

AN XY:

72338

show subpopulations

Gnomad4 AFR

AF:

0.752

Gnomad4 AMR

AF:

0.572

Gnomad4 ASJ

AF:

0.378

Gnomad4 EAS

AF:

0.656

Gnomad4 SAS

AF:

0.595

Gnomad4 FIN

AF:

0.435

Gnomad4 NFE

AF:

0.469

Gnomad4 OTH

AF:

0.510

Alfa

AF:

0.487

Hom.:

38374

Bravo

AF:

0.580

EpiCase

AF:

0.461

EpiControl

AF:

0.445

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Renal tubular dysgenesis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Myocardial infarction, susceptibility to

Benign:1

Benign, no assertion criteria provided

reference population

iDNA Genomics

Oct 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.23

DANN

Benign

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over