NM_000789.4:c.-115C>T

Variant names:

• chr17-63476980-C-T
• rs4292
• NM_000789.4:c.-115C>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.-115C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,067,874 control chromosomes in the GnomAD database, including 221,556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38380 hom., cov: 32)
  • Exomes 𝑓: 0.63 (183176 hom.)
• Consequence: ACE NM_000789.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.577
• Publications: 34 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=-0.58).
• BP6: Variant 17-63476980-C-T is Benign according to our data. Variant chr17-63476980-C-T is described in ClinVar as Benign. ClinVar VariationId is 1285756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.-115C>T		upstream_gene_variant		ENST00000290866.10	NP_000780.1
ACE	NM_001382700.1	c.-350C>T		upstream_gene_variant			NP_001369629.1
ACE	NM_001382701.1	c.-729C>T		upstream_gene_variant			NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.-115C>T		upstream_gene_variant		1	NM_000789.4	ENSP00000290866.4

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106321 AN: 151430 Hom.: 38316 Cov.: 32

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.581

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.674

GnomAD4 exome AF: 0.630 AC: 577373 AN: 916336 Hom.: 183176 AF XY: 0.628 AC XY: 273850 AN XY: 435940

African (AFR) AF: 0.893 AC: 16894 AN: 18918

American (AMR) AF: 0.722 AC: 4975 AN: 6894

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 6343 AN: 11630

East Asian (EAS) AF: 0.634 AC: 14035 AN: 22140

South Asian (SAS) AF: 0.675 AC: 12116 AN: 17954

European-Finnish (FIN) AF: 0.623 AC: 12742 AN: 20450

Middle Eastern (MID) AF: 0.620 AC: 1546 AN: 2494

European-Non Finnish (NFE) AF: 0.623 AC: 485037 AN: 779016

Other (OTH) AF: 0.643 AC: 23685 AN: 36840

GnomAD4 genome AF: 0.702 AC: 106443 AN: 151538 Hom.: 38380 Cov.: 32 AF XY: 0.701 AC XY: 51897 AN XY: 74042

African (AFR) AF: 0.882 AC: 36546 AN: 41442

American (AMR) AF: 0.710 AC: 10850 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1933 AN: 3470

East Asian (EAS) AF: 0.641 AC: 3244 AN: 5058

South Asian (SAS) AF: 0.687 AC: 3307 AN: 4812

European-Finnish (FIN) AF: 0.614 AC: 6447 AN: 10496

Middle Eastern (MID) AF: 0.572 AC: 166 AN: 290

European-Non Finnish (NFE) AF: 0.621 AC: 41999 AN: 67672

Other (OTH) AF: 0.678 AC: 1432 AN: 2112

Alfa AF: 0.667 Hom.: 4284

Bravo AF: 0.715

Asia WGS AF: 0.703 AC: 2423 AN: 3446

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

Jun 18, 2021

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	-0.58
CADD	Benign	16
DANN	Benign	0.94
PhyloP100		0.58
PromoterAI		0.11	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4292; hg19: chr17-61554341;