rs4363

Positions:

Variant summary

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

The NM_000789.4(ACE):c.3692-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,600,104 control chromosomes in the GnomAD database, including 195,701 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20108 hom., cov: 32)

Exomes 𝑓: 0.49 ( 175593 hom. )

Consequence

ACE
NM_000789.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001837

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.08

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 17-63497131-G-A is Benign according to our data. Variant chr17-63497131-G-A is described in ClinVar as [Benign]. Clinvar id is 256806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63497131-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.598 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.3692-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		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.3692-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000789.4	ENSP00000290866	P1	P12821-1

Frequencies

GnomAD3 genomes

AF:

0.512

AC:

77559

AN:

151570

Hom.:

20068

Cov.:

show subpopulations

Gnomad AFR

AF:

0.574

Gnomad AMI

AF:

0.416

Gnomad AMR

AF:

0.547

Gnomad ASJ

AF:

0.353

Gnomad EAS

AF:

0.602

Gnomad SAS

AF:

0.616

Gnomad FIN

AF:

0.461

Gnomad MID

AF:

0.369

Gnomad NFE

AF:

0.471

Gnomad OTH

AF:

0.463

GnomAD3 exomes

AF:

0.521

AC:

118150

AN:

226988

Hom.:

31261

AF XY:

0.517

AC XY:

64571

AN XY:

124874

show subpopulations

Gnomad AFR exome

AF:

0.587

Gnomad AMR exome

AF:

0.594

Gnomad ASJ exome

AF:

0.353

Gnomad EAS exome

AF:

0.610

Gnomad SAS exome

AF:

0.612

Gnomad FIN exome

AF:

0.459

Gnomad NFE exome

AF:

0.473

Gnomad OTH exome

AF:

0.484

GnomAD4 exome

AF:

0.490

AC:

709470

AN:

1448414

Hom.:

175593

Cov.:

AF XY:

0.491

AC XY:

353643

AN XY:

720536

show subpopulations

Gnomad4 AFR exome

AF:

0.575

Gnomad4 AMR exome

AF:

0.587

Gnomad4 ASJ exome

AF:

0.350

Gnomad4 EAS exome

AF:

0.582

Gnomad4 SAS exome

AF:

0.606

Gnomad4 FIN exome

AF:

0.455

Gnomad4 NFE exome

AF:

0.476

Gnomad4 OTH exome

AF:

0.488

GnomAD4 genome

AF:

0.512

AC:

77661

AN:

151690

Hom.:

20108

Cov.:

AF XY:

0.513

AC XY:

38011

AN XY:

74124

show subpopulations

Gnomad4 AFR

AF:

0.574

Gnomad4 AMR

AF:

0.548

Gnomad4 ASJ

AF:

0.353

Gnomad4 EAS

AF:

0.602

Gnomad4 SAS

AF:

0.616

Gnomad4 FIN

AF:

0.461

Gnomad4 NFE

AF:

0.471

Gnomad4 OTH

AF:

0.469

Alfa

AF:

0.483

Hom.:

9091

Bravo

AF:

0.517

Asia WGS

AF:

0.647

AC:

2250

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.2

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.070

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