chr17-63477105-CCTCGGGCCGCCGGGGGCCGG-C

Position:

chr17-63477105-CCTCGGGCCGCCGGGGGCCGG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000789.4(ACE):c.12_31del(p.Ser5AlafsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000304 in 1,317,378 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

ACE
NM_000789.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 0.999

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-63477105-CCTCGGGCCGCCGGGGGCCGG-C is Pathogenic according to our data. Variant chr17-63477105-CCTCGGGCCGCCGGGGGCCGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ACE	NM_000789.4 linkuse as main transcript	c.12_31del	p.Ser5AlafsTer31	frameshift_variant	1/25	ENST00000290866.10	NP_000780.1
ACE	NM_001382700.1 linkuse as main transcript	c.-224_-205del		5_prime_UTR_variant	1/22		NP_001369629.1
ACE	NM_001382701.1 linkuse as main transcript	c.-603_-584del		5_prime_UTR_variant	1/23		NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10 linkuse as main transcript	c.12_31del	p.Ser5AlafsTer31	frameshift_variant	1/25	1	NM_000789.4	ENSP00000290866	P1	P12821-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151282

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.58e-7

AC:

AN:

1165988

Hom.:

AF XY:

0.00000176

AC XY:

AN XY:

566678

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000103

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151390

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74000

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal tubular dysgenesis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 24, 2014

The Ser5AlafsX31 variant in ACE has not been previously reported in individuals with renal tubular dysgenesis and data from large population studies is insufficient to assess the frequency of this variant. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 5 and lead to a premature termination codon 31 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function variants in exon 1 of the ACE gene - encoding the signal peptide - have been associated with renal tubular dysgenesis in homozygous and compound heterozygous individuals (Gribouval 2012). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2018

The c.12_31del20 variant in the ACE gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.12_31del20 variant causes a frameshift starting with codon Serine 5, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 31 of the new reading frame, denoted p.Ser5AlafsX31. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.12_31del20 variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.12_31del20 as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over