rs4305

Variant names:

• chr17-63480868-A-G
• rs4305
• NM_000789.4:c.848-223A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 44 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 -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 VariationId 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 rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.848-223A>G		intron_variant	Intron 5 of 24	ENST00000290866.10	NP_000780.1
ACE	NM_001382700.1	c.375-223A>G		intron_variant	Intron 3 of 21		NP_001369629.1
ACE	NM_001382701.1	c.-5-223A>G		intron_variant	Intron 3 of 22		NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.848-223A>G		intron_variant	Intron 5 of 24	1	NM_000789.4	ENSP00000290866.4

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

African (AFR) AF: 0.195 AC: 8088 AN: 41536

American (AMR) AF: 0.589 AC: 9009 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1615 AN: 3470

East Asian (EAS) AF: 0.640 AC: 3297 AN: 5152

South Asian (SAS) AF: 0.582 AC: 2807 AN: 4824

European-Finnish (FIN) AF: 0.522 AC: 5534 AN: 10606

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37490 AN: 67960

Other (OTH) AF: 0.461 AC: 974 AN: 2112

Alfa AF: 0.435 Hom.: 5302

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

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	-0.84
CADD	Benign	0.92
DANN	Benign	0.75
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4305; hg19: chr17-61558229;