rs4298

Positions:

chr17-63479839-C-T

Variant summary

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

The NM_000789.4(ACE):c.582C>T(p.Asn194=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0817 in 1,613,132 control chromosomes in the GnomAD database, including 8,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2884 hom., cov: 33)

Exomes 𝑓: 0.075 ( 5893 hom. )

Consequence

ACE
NM_000789.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.966

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=-0.74).

BP6

Variant 17-63479839-C-T is Benign according to our data. Variant chr17-63479839-C-T is described in ClinVar as [Benign]. Clinvar id is 256809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.966 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ACE	NM_000789.4 linkuse as main transcript	c.582C>T	p.Asn194=	synonymous_variant	4/25	ENST00000290866.10
ACE	NM_001382700.1 linkuse as main transcript	c.183-498C>T		intron_variant
ACE	NM_001382701.1 linkuse as main transcript	c.-197-498C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACE	ENST00000290866.10 linkuse as main transcript	c.582C>T	p.Asn194=	synonymous_variant	4/25	1	NM_000789.4	P1	P12821-1

Frequencies

GnomAD3 genomes

AF:

0.146

AC:

22292

AN:

152164

Hom.:

2867

Cov.:

show subpopulations

Gnomad AFR

AF:

0.349

Gnomad AMI

AF:

0.164

Gnomad AMR

AF:

0.0724

Gnomad ASJ

AF:

0.0888

Gnomad EAS

AF:

0.00712

Gnomad SAS

AF:

0.0465

Gnomad FIN

AF:

0.0932

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.0691

Gnomad OTH

AF:

0.136

GnomAD3 exomes

AF:

0.0806

AC:

20202

AN:

250574

Hom.:

1516

AF XY:

0.0760

AC XY:

10306

AN XY:

135572

show subpopulations

Gnomad AFR exome

AF:

0.356

Gnomad AMR exome

AF:

0.0479

Gnomad ASJ exome

AF:

0.0801

Gnomad EAS exome

AF:

0.00740

Gnomad SAS exome

AF:

0.0484

Gnomad FIN exome

AF:

0.0949

Gnomad NFE exome

AF:

0.0691

Gnomad OTH exome

AF:

0.0807

GnomAD4 exome

AF:

0.0749

AC:

109418

AN:

1460850

Hom.:

5893

Cov.:

AF XY:

0.0732

AC XY:

53208

AN XY:

726774

show subpopulations

Gnomad4 AFR exome

AF:

0.364

Gnomad4 AMR exome

AF:

0.0516

Gnomad4 ASJ exome

AF:

0.0813

Gnomad4 EAS exome

AF:

0.00650

Gnomad4 SAS exome

AF:

0.0491

Gnomad4 FIN exome

AF:

0.0951

Gnomad4 NFE exome

AF:

0.0695

Gnomad4 OTH exome

AF:

0.0880

GnomAD4 genome

AF:

0.147

AC:

22346

AN:

152282

Hom.:

2884

Cov.:

AF XY:

0.144

AC XY:

10756

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.349

Gnomad4 AMR

AF:

0.0723

Gnomad4 ASJ

AF:

0.0888

Gnomad4 EAS

AF:

0.00694

Gnomad4 SAS

AF:

0.0466

Gnomad4 FIN

AF:

0.0932

Gnomad4 NFE

AF:

0.0691

Gnomad4 OTH

AF:

0.134

Alfa

AF:

0.101

Hom.:

907

Bravo

AF:

0.156

Asia WGS

AF:

0.0550

AC:

191

AN:

3478

EpiCase

AF:

0.0716

EpiControl

AF:

0.0720

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Renal tubular dysgenesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.1

DANN

Benign

0.85

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

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