rs4343

Variant names:

• chr17-63488670-G-A
• rs4343
• NM_000789.4:c.2328G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-63488670-G-A
• chr17-63488670-G-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.2328G>A​(p.Thr776Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 1,608,750 control chromosomes in the GnomAD database, including 207,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24843 hom., cov: 27)
  • Exomes 𝑓: 0.50 (182884 hom.)
• Consequence: ACE NM_000789.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.03

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]

ENSG00000264813 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-63488670-G-A is Benign according to our data. Variant chr17-63488670-G-A is described in ClinVar as [Benign]. Clinvar id is 256803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63488670-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.2328G>A	p.Thr776Thr	synonymous_variant	Exon 16 of 25	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.2328G>A	p.Thr776Thr	synonymous_variant	Exon 16 of 25	1	NM_000789.4	ENSP00000290866.4
ENSG00000264813	ENST00000577647.2	n.606G>A		non_coding_transcript_exon_variant	Exon 5 of 31	2		ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 83465 AN: 148590 Hom.: 24775 Cov.: 27

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.406

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.504

GnomAD2 exomes AF: 0.533 AC: 134087 AN: 251352 AF XY: 0.526

Gnomad AFR exome AF: 0.760

Gnomad AMR exome AF: 0.610

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.670

Gnomad FIN exome AF: 0.445

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.505

GnomAD4 exome AF: 0.496 AC: 723840 AN: 1460046 Hom.: 182884 Cov.: 51 AF XY: 0.496 AC XY: 360156 AN XY: 726438

Gnomad4 AFR exome AF: 0.761 AC: 25480 AN: 33462

Gnomad4 AMR exome AF: 0.605 AC: 27074 AN: 44714

Gnomad4 ASJ exome AF: 0.378 AC: 9861 AN: 26118

Gnomad4 EAS exome AF: 0.649 AC: 25763 AN: 39682

Gnomad4 SAS exome AF: 0.588 AC: 50686 AN: 86214

Gnomad4 FIN exome AF: 0.445 AC: 23744 AN: 53308

Gnomad4 NFE exome AF: 0.476 AC: 528098 AN: 1110458

Gnomad4 Remaining exome AF: 0.508 AC: 30664 AN: 60322

GnomAD4 genome AF: 0.562 AC: 83595 AN: 148704 Hom.: 24843 Cov.: 27 AF XY: 0.560 AC XY: 40536 AN XY: 72338

Gnomad4 AFR AF: 0.752 AC: 0.751857 AN: 0.751857

Gnomad4 AMR AF: 0.572 AC: 0.57203 AN: 0.57203

Gnomad4 ASJ AF: 0.378 AC: 0.378198 AN: 0.378198

Gnomad4 EAS AF: 0.656 AC: 0.65566 AN: 0.65566

Gnomad4 SAS AF: 0.595 AC: 0.595403 AN: 0.595403

Gnomad4 FIN AF: 0.435 AC: 0.43489 AN: 0.43489

Gnomad4 NFE AF: 0.469 AC: 0.468812 AN: 0.468812

Gnomad4 OTH AF: 0.510 AC: 0.510145 AN: 0.510145

Alfa AF: 0.505 Hom.: 85436

Bravo AF: 0.580

EpiCase AF: 0.461

EpiControl AF: 0.445

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal tubular dysgenesis Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myocardial infarction, susceptibility to Benign:1

Oct 11, 2021

iDNA Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.23
DANN	Benign	0.44
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs4343; hg19: chr17-61566031; COSMIC: COSV52007462; COSMIC: COSV52007462;