rs4362

Variant names:

• chr17-63496400-T-C
• rs4362
• NM_000789.4:c.3387T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-63496400-T-C
• chr17-63496400-T-A
• chr17-63496400-T-G

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.3387T>C​(p.Phe1129Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,613,968 control chromosomes in the GnomAD database, including 200,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20476 hom., cov: 34)
  • Exomes 𝑓: 0.49 (180509 hom.)
• Consequence: ACE NM_000789.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.87
• Publications: 86 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

ENSG00000264813 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-63496400-T-C is Benign according to our data. Variant chr17-63496400-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.607 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.3387T>C	p.Phe1129Phe	synonymous	Exon 23 of 25	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.2820T>C	p.Phe940Phe	synonymous	Exon 20 of 22	NP_001369629.1
	ACE	NM_001382701.1		c.2535T>C	p.Phe845Phe	synonymous	Exon 21 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.3387T>C	p.Phe1129Phe	synonymous	Exon 23 of 25	ENSP00000290866.4	P12821-1
	ACE	ENST00000290863.10	TSL:1	c.1665T>C	p.Phe555Phe	synonymous	Exon 12 of 14	ENSP00000290863.6	P12821-3
	ENSG00000264813	ENST00000577647.2	TSL:2	n.1665T>C		non_coding_transcript_exon	Exon 12 of 31	ENSP00000464149.1	F6X3S4

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78371 AN: 152026 Hom.: 20431 Cov.: 34

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.468

GnomAD2 exomes AF: 0.522 AC: 131102 AN: 251312 AF XY: 0.518

Gnomad AFR exome AF: 0.587

Gnomad AMR exome AF: 0.599

Gnomad ASJ exome AF: 0.372

Gnomad EAS exome AF: 0.609

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.494

GnomAD4 exome AF: 0.494 AC: 722442 AN: 1461824 Hom.: 180509 Cov.: 73 AF XY: 0.495 AC XY: 360243 AN XY: 727218

African (AFR) AF: 0.576 AC: 19296 AN: 33478

American (AMR) AF: 0.593 AC: 26504 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 9749 AN: 26136

East Asian (EAS) AF: 0.584 AC: 23177 AN: 39698

South Asian (SAS) AF: 0.613 AC: 52830 AN: 86238

European-Finnish (FIN) AF: 0.458 AC: 24450 AN: 53404

Middle Eastern (MID) AF: 0.411 AC: 2373 AN: 5768

European-Non Finnish (NFE) AF: 0.480 AC: 534026 AN: 1111986

Other (OTH) AF: 0.497 AC: 30037 AN: 60396

GnomAD4 genome AF: 0.516 AC: 78475 AN: 152144 Hom.: 20476 Cov.: 34 AF XY: 0.516 AC XY: 38407 AN XY: 74382

African (AFR) AF: 0.575 AC: 23884 AN: 41518

American (AMR) AF: 0.555 AC: 8483 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1298 AN: 3470

East Asian (EAS) AF: 0.603 AC: 3104 AN: 5146

South Asian (SAS) AF: 0.626 AC: 3020 AN: 4824

European-Finnish (FIN) AF: 0.461 AC: 4882 AN: 10596

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32305 AN: 67978

Other (OTH) AF: 0.474 AC: 1002 AN: 2112

Alfa AF: 0.487 Hom.: 76528

Bravo AF: 0.521

Asia WGS AF: 0.650 AC: 2260 AN: 3478

EpiCase AF: 0.465

EpiControl AF: 0.448

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Renal tubular dysgenesis (2)
-	-	1	Microvascular complications of diabetes, susceptibility to, 3;C3281105:Hemorrhage, intracerebral, susceptibility to;C5681536:Renal tubular dysgenesis of genetic origin (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.46
DANN	Benign	0.42
PhyloP100		-1.9
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: rs4362; hg19: chr17-61573761; COSMIC: COSV52003393; COSMIC: COSV52003393;