Genetic Variant ACE:c.-115C>T (chr17-63476980-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000789.4(ACE):c.-115C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,067,874 control chromosomes in the GnomAD database, including 221,556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 38380 hom., cov: 32)

Exomes 𝑓: 0.63 ( 183176 hom. )

Consequence

ACE
NM_000789.4 upstream_gene

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.577

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 17-63476980-C-T is Benign according to our data. Variant chr17-63476980-C-T is described in ClinVar as [Benign]. Clinvar id is 1285756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
ACE	NM_000789.4 link	c.-115C>T	upstream_gene_variant	ENST00000290866.10	NP_000780.1	P12821-1B4DKH4
ACE	NM_001382700.1 link	c.-350C>T	upstream_gene_variant		NP_001369629.1
ACE	NM_001382701.1 link	c.-729C>T	upstream_gene_variant		NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10 link	c.-115C>T		upstream_gene_variant		1	NM_000789.4	ENSP00000290866.4		P12821-1

Frequencies

GnomAD3 genomes

AF:

0.702

AC:

106321

AN:

151430

Hom.:

38316

Cov.:

show subpopulations

Gnomad AFR

AF:

0.882

Gnomad AMI

AF:

0.573

Gnomad AMR

AF:

0.710

Gnomad ASJ

AF:

0.557

Gnomad EAS

AF:

0.642

Gnomad SAS

AF:

0.686

Gnomad FIN

AF:

0.614

Gnomad MID

AF:

0.581

Gnomad NFE

AF:

0.621

Gnomad OTH

AF:

0.674

GnomAD4 exome

AF:

0.630

AC:

577373

AN:

916336

Hom.:

183176

AF XY:

0.628

AC XY:

273850

AN XY:

435940

show subpopulations

Gnomad4 AFR exome

AF:

0.893

Gnomad4 AMR exome

AF:

0.722

Gnomad4 ASJ exome

AF:

0.545

Gnomad4 EAS exome

AF:

0.634

Gnomad4 SAS exome

AF:

0.675

Gnomad4 FIN exome

AF:

0.623

Gnomad4 NFE exome

AF:

0.623

Gnomad4 OTH exome

AF:

0.643

GnomAD4 genome

AF:

0.702

AC:

106443

AN:

151538

Hom.:

38380

Cov.:

AF XY:

0.701

AC XY:

51897

AN XY:

74042

show subpopulations

Gnomad4 AFR

AF:

0.882

Gnomad4 AMR

AF:

0.710

Gnomad4 ASJ

AF:

0.557

Gnomad4 EAS

AF:

0.641

Gnomad4 SAS

AF:

0.687

Gnomad4 FIN

AF:

0.614

Gnomad4 NFE

AF:

0.621

Gnomad4 OTH

AF:

0.678

Alfa

AF:

0.667

Hom.:

4284

Bravo

AF:

0.715

Asia WGS

AF:

0.703

AC:

2423

AN:

3446

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.94

Splicing

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