17-63494982-T-C

Variant names:

• chr17-63494982-T-C
• rs4359
• NM_000789.4:c.3380+512T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000789.4(ACE):​c.3380+512T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 151,976 control chromosomes in the GnomAD database, including 19,904 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (19904 hom., cov: 32)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130
• Publications: 25 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.3380+512T>C		intron_variant	Intron 22 of 24	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.3380+512T>C		intron_variant	Intron 22 of 24	1	NM_000789.4	ENSP00000290866.4
ENSG00000264813	ENST00000577647.2	n.1658+512T>C		intron_variant	Intron 11 of 30	2		ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77171 AN: 151858 Hom.: 19867 Cov.: 32

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.455

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.508 AC: 77266 AN: 151976 Hom.: 19904 Cov.: 32 AF XY: 0.509 AC XY: 37763 AN XY: 74256

African (AFR) AF: 0.572 AC: 23683 AN: 41430

American (AMR) AF: 0.541 AC: 8253 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1252 AN: 3470

East Asian (EAS) AF: 0.605 AC: 3130 AN: 5172

South Asian (SAS) AF: 0.611 AC: 2943 AN: 4820

European-Finnish (FIN) AF: 0.458 AC: 4845 AN: 10572

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.467 AC: 31710 AN: 67932

Other (OTH) AF: 0.462 AC: 973 AN: 2108

Alfa AF: 0.484 Hom.: 49161

Bravo AF: 0.513

Asia WGS AF: 0.643 AC: 2235 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.2
DANN	Benign	0.34
PhyloP100		-0.013
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: rs4359; hg19: chr17-61572343;