rs4309

Variant names:

• chr17-63482562-C-T
• rs4309
• NM_000789.4:c.1215C>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.1215C>T​(p.Pro405Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,613,878 control chromosomes in the GnomAD database, including 155,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11850 hom., cov: 32)
  • Exomes 𝑓: 0.44 (143412 hom.)
• Consequence: ACE NM_000789.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.05
• Publications: 74 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 17-63482562-C-T is Benign according to our data. Variant chr17-63482562-C-T is described in ClinVar as Benign. ClinVar VariationId is 256799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 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.1215C>T	p.Pro405Pro	synonymous	Exon 8 of 25	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.648C>T	p.Pro216Pro	synonymous	Exon 5 of 22	NP_001369629.1
	ACE	NM_001382701.1		c.363C>T	p.Pro121Pro	synonymous	Exon 6 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.1215C>T	p.Pro405Pro	synonymous	Exon 8 of 25	ENSP00000290866.4	P12821-1
	ACE	ENST00000953328.1		c.1215C>T	p.Pro405Pro	synonymous	Exon 8 of 25	ENSP00000623387.1
	ACE	ENST00000884279.1		c.1215C>T	p.Pro405Pro	synonymous	Exon 8 of 25	ENSP00000554338.1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56212 AN: 152006 Hom.: 11840 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.363

GnomAD2 exomes AF: 0.457 AC: 114893 AN: 251344 AF XY: 0.459

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.598

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.651

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.439

GnomAD4 exome AF: 0.437 AC: 638970 AN: 1461754 Hom.: 143412 Cov.: 58 AF XY: 0.439 AC XY: 319176 AN XY: 727194

African (AFR) AF: 0.148 AC: 4964 AN: 33480

American (AMR) AF: 0.586 AC: 26199 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9237 AN: 26134

East Asian (EAS) AF: 0.611 AC: 24268 AN: 39700

South Asian (SAS) AF: 0.534 AC: 46042 AN: 86254

European-Finnish (FIN) AF: 0.386 AC: 20576 AN: 53352

Middle Eastern (MID) AF: 0.333 AC: 1918 AN: 5768

European-Non Finnish (NFE) AF: 0.432 AC: 480173 AN: 1111962

Other (OTH) AF: 0.424 AC: 25593 AN: 60384

GnomAD4 genome AF: 0.370 AC: 56231 AN: 152124 Hom.: 11850 Cov.: 32 AF XY: 0.375 AC XY: 27902 AN XY: 74368

African (AFR) AF: 0.167 AC: 6944 AN: 41520

American (AMR) AF: 0.498 AC: 7619 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1240 AN: 3470

East Asian (EAS) AF: 0.647 AC: 3325 AN: 5142

South Asian (SAS) AF: 0.539 AC: 2596 AN: 4820

European-Finnish (FIN) AF: 0.388 AC: 4108 AN: 10590

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29228 AN: 67974

Other (OTH) AF: 0.360 AC: 758 AN: 2106

Alfa AF: 0.411 Hom.: 49242

Bravo AF: 0.363

Asia WGS AF: 0.568 AC: 1974 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.409

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Renal tubular dysgenesis (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.36
DANN	Benign	0.88
PhyloP100		-4.1
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: rs4309; hg19: chr17-61559923; COSMIC: COSV52007384; COSMIC: COSV52007384;