rs4298

Variant names:

• chr17-63479839-C-T
• rs4298
• NM_000789.4:c.582C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000789.4(ACE):​c.582C>T​(p.Asn194Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0817 in 1,613,132 control chromosomes in the GnomAD database, including 8,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2884 hom., cov: 33)
  • Exomes 𝑓: 0.075 (5893 hom.)
• Consequence: ACE NM_000789.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.966
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 17-63479839-C-T is Benign according to our data. Variant chr17-63479839-C-T is described in ClinVar as Benign. ClinVar VariationId is 256809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.966 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.344 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.582C>T	p.Asn194Asn	synonymous	Exon 4 of 25	NP_000780.1
	ACE	NM_001382700.1		c.183-498C>T		intron	N/A	NP_001369629.1
	ACE	NM_001382701.1		c.-197-498C>T		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.582C>T	p.Asn194Asn	synonymous	Exon 4 of 25	ENSP00000290866.4
	ACE	ENST00000953328.1		c.582C>T	p.Asn194Asn	synonymous	Exon 4 of 25	ENSP00000623387.1
	ACE	ENST00000884279.1		c.582C>T	p.Asn194Asn	synonymous	Exon 4 of 25	ENSP00000554338.1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22292 AN: 152164 Hom.: 2867 Cov.: 33

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.0724

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.00712

Gnomad SAS AF: 0.0465

Gnomad FIN AF: 0.0932

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0691

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.0806 AC: 20202 AN: 250574 AF XY: 0.0760

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.0479

Gnomad ASJ exome AF: 0.0801

Gnomad EAS exome AF: 0.00740

Gnomad FIN exome AF: 0.0949

Gnomad NFE exome AF: 0.0691

Gnomad OTH exome AF: 0.0807

GnomAD4 exome AF: 0.0749 AC: 109418 AN: 1460850 Hom.: 5893 Cov.: 33 AF XY: 0.0732 AC XY: 53208 AN XY: 726774

African (AFR) AF: 0.364 AC: 12174 AN: 33478

American (AMR) AF: 0.0516 AC: 2309 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 2125 AN: 26136

East Asian (EAS) AF: 0.00650 AC: 258 AN: 39700

South Asian (SAS) AF: 0.0491 AC: 4235 AN: 86258

European-Finnish (FIN) AF: 0.0951 AC: 4986 AN: 52404

Middle Eastern (MID) AF: 0.132 AC: 760 AN: 5768

European-Non Finnish (NFE) AF: 0.0695 AC: 77255 AN: 1111992

Other (OTH) AF: 0.0880 AC: 5316 AN: 60390

GnomAD4 genome AF: 0.147 AC: 22346 AN: 152282 Hom.: 2884 Cov.: 33 AF XY: 0.144 AC XY: 10756 AN XY: 74460

African (AFR) AF: 0.349 AC: 14500 AN: 41540

American (AMR) AF: 0.0723 AC: 1106 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3470

East Asian (EAS) AF: 0.00694 AC: 36 AN: 5184

South Asian (SAS) AF: 0.0466 AC: 225 AN: 4830

European-Finnish (FIN) AF: 0.0932 AC: 990 AN: 10620

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0691 AC: 4700 AN: 68022

Other (OTH) AF: 0.134 AC: 284 AN: 2112

Alfa AF: 0.102 Hom.: 1013

Bravo AF: 0.156

Asia WGS AF: 0.0550 AC: 191 AN: 3478

EpiCase AF: 0.0716

EpiControl AF: 0.0720

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Renal tubular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.1
DANN	Benign	0.85
PhyloP100		-0.97
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: rs4298; hg19: chr17-61557200; COSMIC: COSV52023921; COSMIC: COSV52023921;