17-63488713-C-T

Variant names:

• chr17-63488713-C-T
• rs397514689
• NM_000789.4:c.2371C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000789.4(ACE):​c.2371C>T​(p.Arg791*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ACE NM_000789.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.674

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

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-63488713-C-T is Pathogenic according to our data. Variant chr17-63488713-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 50209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63488713-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.2371C>T	p.Arg791*	stop_gained	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.2371C>T	p.Arg791*	stop_gained	Exon 16 of 25	1	NM_000789.4	ENSP00000290866.4
ENSG00000264813	ENST00000577647.2	n.649C>T		non_coding_transcript_exon_variant	Exon 5 of 31	2		ENSP00000464149.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251468 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461864 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg791*) in the ACE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACE are known to be pathogenic (PMID: 22095942). This variant is present in population databases (rs397514689, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with renal tubular dysgenesis (PMID: 22095942). ClinVar contains an entry for this variant (Variation ID: 50209). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

May 25, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R791X pathogenic variant in the ACE gene has been reported previously in the homozygous state in association with renal tubular dysgenesis (Gribouval et al., 2012).This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies of the R791X mutation (aka R762X using alternate nomenclature) indicate that although it exhibits N-domain enzyme activity, it lacks the C-domain activity and is not properly inserted in the plasma membrane (Michaud et al., 2014). The R791X mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R791X as a pathogenic variant. This variant has been seen Paternally inherited. -

Microvascular complications of diabetes, susceptibility to, 3;C3281105:Hemorrhage, intracerebral, susceptibility to;C5681536:Renal tubular dysgenesis of genetic origin Pathogenic:1

Sep 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal tubular dysgenesis Pathogenic:1

Feb 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.97
GERP RS		2.5

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514689; hg19: chr17-61566074; COSMIC: COSV52009500; COSMIC: COSV52009500;