rs532464035

Variant names:

• chr17-63484927-C-A
• rs532464035
• ENST00000290863.10:c.60C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-63484927-C-A
• chr17-63484927-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_152830.3(ACE):​c.60C>A​(p.Tyr20*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,106 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 Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACE NM_152830.3 stop_gained
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -1.74
• Publications: 1 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 of genetic origin

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intracerebral hemorrhage

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264813 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152830.3. 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.1922-309C>A		intron	N/A	NP_000780.1
	ACE	NM_152830.3		c.60C>A	p.Tyr20*	stop_gained	Exon 1 of 14	NP_690043.1
	ACE	NM_001178057.2		c.60C>A	p.Tyr20*	stop_gained	Exon 1 of 13	NP_001171528.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	ENST00000290863.10	TSL:1	c.60C>A	p.Tyr20*	stop_gained	Exon 1 of 14	ENSP00000290863.6
	ACE	ENST00000290866.10	TSL:1 MANE Select	c.1922-309C>A		intron	N/A	ENSP00000290866.4
	ENSG00000264813	ENST00000577647.2	TSL:2	n.60C>A		non_coding_transcript_exon	Exon 1 of 31	ENSP00000464149.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444106 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 716670

African (AFR) AF: 0.00 AC: 0 AN: 33100

American (AMR) AF: 0.00 AC: 0 AN: 41890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 38786

South Asian (SAS) AF: 0.00 AC: 0 AN: 83210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1103572

Other (OTH) AF: 0.00 AC: 0 AN: 59832

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	1.3
DANN	Uncertain	0.99
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.20	N
PhyloP100		-1.7
Vest4		0.52
GERP RS		-1.1
PromoterAI		0.015	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 24

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

Other links and lift over

dbSNP: rs532464035; hg19: chr17-61562288;