rs4305

chr17-63480868-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000789.4(ACE):c.848-223A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 152,166 control chromosomes in the GnomAD database, including 17,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.46 (17854 hom., cov: 33)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.253

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-63480868-A-G is Benign according to our data. Variant chr17-63480868-A-G is described in ClinVar as [Benign]. Clinvar id is 1278455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACE	NM_000789.4	c.848-223A>G		intron_variant		ENST00000290866.10
ACE	NM_001382700.1	c.375-223A>G		intron_variant
ACE	NM_001382701.1	c.-5-223A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACE	ENST00000290866.10	c.848-223A>G		intron_variant		1	NM_000789.4	P1

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69278 AN: 152048 Hom.: 17845 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.465

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.455 AC: 69299 AN: 152166 Hom.: 17854 Cov.: 33 AF XY: 0.459 AC XY: 34152 AN XY: 74382

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.589

Gnomad4 ASJ AF: 0.465

Gnomad4 EAS AF: 0.640

Gnomad4 SAS AF: 0.582

Gnomad4 FIN AF: 0.522

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.461

Alfa AF: 0.512 Hom.: 4162

Bravo AF: 0.444

Asia WGS AF: 0.585 AC: 2032 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.92
Dann	Benign	0.75

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

Other links and lift over

dbSNP: rs4305; hg19: chr17-61558229;