17-63485912-C-G

Variant names:

• chr17-63485912-C-G
• rs4327
• NM_000789.4:c.2058+540C>G

Variant summary

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

The NM_000789.4(ACE):​c.2058+540C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 194,902 control chromosomes in the GnomAD database, including 21,394 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 (16578 hom., cov: 32)
  • Exomes 𝑓: 0.45 (4816 hom.)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 9 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 - ACE

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• renal tubular dysgenesis of genetic origin

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, 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 (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000789.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	NM_000789.4	MANE Select	c.2058+540C>G		intron	N/A	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.1491+540C>G		intron	N/A	NP_001369629.1
	ACE	NM_001382701.1		c.1206+540C>G		intron	N/A	NP_001369630.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	ENST00000290866.10	TSL:1 MANE Select	c.2058+540C>G		intron	N/A	ENSP00000290866.4	P12821-1
	ACE	ENST00000290863.10	TSL:1	c.336+540C>G		intron	N/A	ENSP00000290863.6	P12821-3
	ENSG00000264813	ENST00000577647.2	TSL:2	n.336+540C>G		intron	N/A	ENSP00000464149.1	F6X3S4

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70348 AN: 151832 Hom.: 16549 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.420

GnomAD4 exome AF: 0.453 AC: 19463 AN: 42952 Hom.: 4816 AF XY: 0.456 AC XY: 10134 AN XY: 22204

African (AFR) AF: 0.357 AC: 286 AN: 800

American (AMR) AF: 0.530 AC: 1879 AN: 3544

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 252 AN: 848

East Asian (EAS) AF: 0.625 AC: 1485 AN: 2376

South Asian (SAS) AF: 0.529 AC: 2930 AN: 5538

European-Finnish (FIN) AF: 0.396 AC: 609 AN: 1536

Middle Eastern (MID) AF: 0.352 AC: 45 AN: 128

European-Non Finnish (NFE) AF: 0.427 AC: 11110 AN: 26048

Other (OTH) AF: 0.406 AC: 867 AN: 2134

GnomAD4 genome AF: 0.463 AC: 70413 AN: 151950 Hom.: 16578 Cov.: 32 AF XY: 0.466 AC XY: 34612 AN XY: 74242

African (AFR) AF: 0.417 AC: 17283 AN: 41412

American (AMR) AF: 0.522 AC: 7954 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1274 AN: 3462

East Asian (EAS) AF: 0.663 AC: 3432 AN: 5178

South Asian (SAS) AF: 0.593 AC: 2862 AN: 4824

European-Finnish (FIN) AF: 0.448 AC: 4723 AN: 10552

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.464 AC: 31515 AN: 67966

Other (OTH) AF: 0.426 AC: 899 AN: 2110

Alfa AF: 0.458 Hom.: 1931

Bravo AF: 0.461

Asia WGS AF: 0.635 AC: 2208 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.2
DANN	Benign	0.45
PhyloP100		-1.0
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: rs4327; hg19: chr17-61563273;