NM_000789.4:c.2058+438A>G

Variant names:

• chr17-63485810-A-G
• rs4324
• NM_000789.4:c.2058+438A>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+438A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 243,108 control chromosomes in the GnomAD database, including 26,211 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 (16109 hom., cov: 27)
  • Exomes 𝑓: 0.44 (10102 hom.)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.131
• Publications: 16 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.2058+438A>G		intron_variant	Intron 13 of 24	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.2058+438A>G		intron_variant	Intron 13 of 24	1	NM_000789.4	ENSP00000290866.4
ENSG00000264813	ENST00000577647.2	n.336+438A>G		intron_variant	Intron 2 of 30	2		ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 68691 AN: 149190 Hom.: 16080 Cov.: 27

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.416

GnomAD4 exome AF: 0.444 AC: 41666 AN: 93816 Hom.: 10102 Cov.: 0 AF XY: 0.449 AC XY: 22261 AN XY: 49600

African (AFR) AF: 0.352 AC: 865 AN: 2460

American (AMR) AF: 0.524 AC: 2090 AN: 3986

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 717 AN: 2284

East Asian (EAS) AF: 0.633 AC: 2599 AN: 4108

South Asian (SAS) AF: 0.518 AC: 7815 AN: 15080

European-Finnish (FIN) AF: 0.392 AC: 1610 AN: 4104

Middle Eastern (MID) AF: 0.350 AC: 117 AN: 334

European-Non Finnish (NFE) AF: 0.421 AC: 23936 AN: 56906

Other (OTH) AF: 0.421 AC: 1917 AN: 4554

GnomAD4 genome AF: 0.461 AC: 68753 AN: 149292 Hom.: 16109 Cov.: 27 AF XY: 0.462 AC XY: 33478 AN XY: 72426

African (AFR) AF: 0.415 AC: 16908 AN: 40696

American (AMR) AF: 0.516 AC: 7635 AN: 14784

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1277 AN: 3460

East Asian (EAS) AF: 0.661 AC: 3317 AN: 5018

South Asian (SAS) AF: 0.593 AC: 2815 AN: 4748

European-Finnish (FIN) AF: 0.431 AC: 4127 AN: 9576

Middle Eastern (MID) AF: 0.310 AC: 90 AN: 290

European-Non Finnish (NFE) AF: 0.463 AC: 31324 AN: 67722

Other (OTH) AF: 0.423 AC: 883 AN: 2088

Alfa AF: 0.446 Hom.: 3422

Bravo AF: 0.461

Asia WGS AF: 0.634 AC: 2205 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.2
DANN	Benign	0.40
PhyloP100		-0.13
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: rs4324; hg19: chr17-61563171;