rs4334

Variant names:

• chr17-63487579-A-C
• rs4334
• NM_000789.4:c.2305+506A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-63487579-A-C
• chr17-63487579-A-G
• chr17-63487579-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.2305+506A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 151,604 control chromosomes in the GnomAD database, including 16,588 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 (16588 hom., cov: 31)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.645
• Publications: 10 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.2305+506A>C		intron_variant	Intron 15 of 24	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.2305+506A>C		intron_variant	Intron 15 of 24	1	NM_000789.4	ENSP00000290866.4
ENSG00000264813	ENST00000577647.2	n.583+506A>C		intron_variant	Intron 4 of 30	2		ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70360 AN: 151484 Hom.: 16559 Cov.: 31

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.423

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

GnomAD4 genome AF: 0.465 AC: 70425 AN: 151604 Hom.: 16588 Cov.: 31 AF XY: 0.468 AC XY: 34614 AN XY: 74032

African (AFR) AF: 0.417 AC: 17243 AN: 41306

American (AMR) AF: 0.523 AC: 7970 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1274 AN: 3464

East Asian (EAS) AF: 0.665 AC: 3409 AN: 5130

South Asian (SAS) AF: 0.596 AC: 2864 AN: 4806

European-Finnish (FIN) AF: 0.449 AC: 4725 AN: 10518

Middle Eastern (MID) AF: 0.325 AC: 95 AN: 292

European-Non Finnish (NFE) AF: 0.465 AC: 31563 AN: 67838

Other (OTH) AF: 0.429 AC: 903 AN: 2104

Alfa AF: 0.447 Hom.: 3401

Bravo AF: 0.461

Asia WGS AF: 0.637 AC: 2213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.47
PhyloP100		-0.65
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: rs4334; hg19: chr17-61564940;