rs4353

Variant names:

• chr17-63493061-A-G
• rs4353
• NM_000789.4:c.2913-375A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-63493061-A-G
• chr17-63493061-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000789.4(ACE):​c.2913-375A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 151,998 control chromosomes in the GnomAD database, including 16,299 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (16299 hom., cov: 32)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.118
• 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

ENSG00000264813 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.2913-375A>G		intron_variant	Intron 19 of 24	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.2913-375A>G		intron_variant	Intron 19 of 24	1	NM_000789.4	ENSP00000290866.4
ENSG00000264813	ENST00000577647.2	n.1191-375A>G		intron_variant	Intron 8 of 30	2		ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69761 AN: 151880 Hom.: 16269 Cov.: 32

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.420

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

GnomAD4 genome AF: 0.459 AC: 69830 AN: 151998 Hom.: 16299 Cov.: 32 AF XY: 0.462 AC XY: 34296 AN XY: 74300

African (AFR) AF: 0.395 AC: 16355 AN: 41438

American (AMR) AF: 0.520 AC: 7943 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1254 AN: 3470

East Asian (EAS) AF: 0.606 AC: 3122 AN: 5156

South Asian (SAS) AF: 0.607 AC: 2923 AN: 4816

European-Finnish (FIN) AF: 0.459 AC: 4847 AN: 10564

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32003 AN: 67950

Other (OTH) AF: 0.427 AC: 902 AN: 2114

Alfa AF: 0.454 Hom.: 27737

Bravo AF: 0.455

Asia WGS AF: 0.630 AC: 2190 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.0
DANN	Benign	0.36
PhyloP100		0.12
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: rs4353; hg19: chr17-61570422;