rs4308

Variant names:

• chr17-63482264-A-G
• rs4308
• NM_000789.4:c.1119-202A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-63482264-A-G
• chr17-63482264-A-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.1119-202A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 151,614 control chromosomes in the GnomAD database, including 39,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.71 (39548 hom., cov: 29)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0590
• Publications: 30 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=-1.06).
• BP6: Variant 17-63482264-A-G is Benign according to our data. Variant chr17-63482264-A-G is described in ClinVar as Benign. ClinVar VariationId is 1260757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.1119-202A>G		intron_variant	Intron 7 of 24	ENST00000290866.10	NP_000780.1
ACE	NM_001382700.1	c.473-123A>G		intron_variant	Intron 4 of 21		NP_001369629.1
ACE	NM_001382701.1	c.267-202A>G		intron_variant	Intron 5 of 22		NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.1119-202A>G		intron_variant	Intron 7 of 24	1	NM_000789.4	ENSP00000290866.4
ACE	ENST00000428043.5	c.1119-202A>G		intron_variant	Intron 7 of 23	2		ENSP00000397593.2
ACE	ENST00000582678.5	n.*518-202A>G		intron_variant	Intron 6 of 11	2		ENSP00000462995.1
ACE	ENST00000584529.5	n.1153-202A>G		intron_variant	Intron 7 of 8	2

Frequencies

GnomAD3 genomes AF: 0.711 AC: 107751 AN: 151496 Hom.: 39478 Cov.: 29

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.677

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

GnomAD4 genome AF: 0.712 AC: 107885 AN: 151614 Hom.: 39548 Cov.: 29 AF XY: 0.710 AC XY: 52585 AN XY: 74054

African (AFR) AF: 0.908 AC: 37552 AN: 41378

American (AMR) AF: 0.714 AC: 10898 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1942 AN: 3470

East Asian (EAS) AF: 0.666 AC: 3402 AN: 5106

South Asian (SAS) AF: 0.688 AC: 3308 AN: 4808

European-Finnish (FIN) AF: 0.616 AC: 6447 AN: 10472

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.623 AC: 42218 AN: 67820

Other (OTH) AF: 0.680 AC: 1430 AN: 2104

Alfa AF: 0.706 Hom.: 4981

Bravo AF: 0.725

Asia WGS AF: 0.711 AC: 2472 AN: 3476

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	-1.1
CADD	Benign	0.50
DANN	Benign	0.44
PhyloP100		-0.059
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: rs4308; hg19: chr17-61559625;