NM_000789.4:c.19C>T

Variant names:

• chr17-63477113-C-T
• rs1285068027
• NM_000789.4:c.19C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000789.4(ACE):​c.19C>T​(p.Arg7Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000766 in 1,175,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: ACE NM_000789.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.310
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097383976).

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.19C>T	p.Arg7Cys	missense	Exon 1 of 25	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.-217C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 22	NP_001369629.1
	ACE	NM_001382701.1		c.-596C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_001369630.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	ENST00000290866.10	TSL:1 MANE Select	c.19C>T	p.Arg7Cys	missense	Exon 1 of 25	ENSP00000290866.4	P12821-1
	ACE	ENST00000953328.1		c.19C>T	p.Arg7Cys	missense	Exon 1 of 25	ENSP00000623387.1
	ACE	ENST00000884279.1		c.19C>T	p.Arg7Cys	missense	Exon 1 of 25	ENSP00000554338.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000766 AC: 9 AN: 1175640 Hom.: 0 Cov.: 28 AF XY: 0.00000699 AC XY: 4 AN XY: 572296

African (AFR) AF: 0.0000434 AC: 1 AN: 23068

American (AMR) AF: 0.00 AC: 0 AN: 9154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15410

East Asian (EAS) AF: 0.00 AC: 0 AN: 26136

South Asian (SAS) AF: 0.00 AC: 0 AN: 44316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27650

Middle Eastern (MID) AF: 0.000309 AC: 1 AN: 3236

European-Non Finnish (NFE) AF: 0.00000715 AC: 7 AN: 978950

Other (OTH) AF: 0.00 AC: 0 AN: 47720

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Microvascular complications of diabetes, susceptibility to, 3;C3281105:Hemorrhage, intracerebral, susceptibility to;C5681536:Renal tubular dysgenesis of genetic origin (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.31
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.032
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.23		Loss of methylation at R7 (P = 0.0064)
MVP		0.44
MPC		0.13
ClinPred		0.28	T
GERP RS		0.92
PromoterAI		-0.066	Neutral
Varity_R		0.13
gMVP		0.36
Mutation Taster		=87/13	polymorphism

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: rs1285068027; hg19: chr17-61554474;