rs4293

Variant names:

• chr17-63478305-G-A
• rs4293
• NM_000789.4:c.417+207G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-63478305-G-A
• chr17-63478305-G-C
• chr17-63478305-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000789.4(ACE):​c.417+207G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 660,340 control chromosomes in the GnomAD database, including 93,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17672 hom., cov: 33)
  • Exomes 𝑓: 0.54 (76241 hom.)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.675
• Publications: 25 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-63478305-G-A is Benign according to our data. Variant chr17-63478305-G-A is described in ClinVar as Benign. ClinVar VariationId is 1262835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.417+207G>A		intron_variant	Intron 2 of 24	ENST00000290866.10	NP_000780.1
ACE	NM_001382700.1	c.182+207G>A		intron_variant	Intron 2 of 21		NP_001369629.1
ACE	NM_001382701.1	c.-198+207G>A		intron_variant	Intron 2 of 22		NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.417+207G>A		intron_variant	Intron 2 of 24	1	NM_000789.4	ENSP00000290866.4

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68924 AN: 152030 Hom.: 17663 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.461

GnomAD4 exome AF: 0.542 AC: 275439 AN: 508192 Hom.: 76241 Cov.: 6 AF XY: 0.543 AC XY: 143369 AN XY: 263880

African (AFR) AF: 0.181 AC: 2449 AN: 13522

American (AMR) AF: 0.628 AC: 11622 AN: 18506

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 6432 AN: 13916

East Asian (EAS) AF: 0.627 AC: 19381 AN: 30888

South Asian (SAS) AF: 0.576 AC: 26741 AN: 46434

European-Finnish (FIN) AF: 0.528 AC: 15187 AN: 28744

Middle Eastern (MID) AF: 0.459 AC: 942 AN: 2052

European-Non Finnish (NFE) AF: 0.546 AC: 178280 AN: 326326

Other (OTH) AF: 0.518 AC: 14405 AN: 27804

GnomAD4 genome AF: 0.453 AC: 68946 AN: 152148 Hom.: 17672 Cov.: 33 AF XY: 0.457 AC XY: 33989 AN XY: 74374

African (AFR) AF: 0.194 AC: 8067 AN: 41516

American (AMR) AF: 0.585 AC: 8949 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 1610 AN: 3470

East Asian (EAS) AF: 0.635 AC: 3279 AN: 5164

South Asian (SAS) AF: 0.578 AC: 2790 AN: 4824

European-Finnish (FIN) AF: 0.522 AC: 5526 AN: 10590

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.548 AC: 37278 AN: 67974

Other (OTH) AF: 0.457 AC: 965 AN: 2110

Alfa AF: 0.401 Hom.: 3817

Bravo AF: 0.441

Asia WGS AF: 0.583 AC: 2026 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.0
DANN	Benign	0.47
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4293; hg19: chr17-61555666;