chr17-63478937-C-G

Position:

• chr17-63478937-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000789.4(ACE):​c.418-70C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 1,362,354 control chromosomes in the GnomAD database, including 265,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (28807 hom., cov: 31)
  • Exomes 𝑓: 0.62 (236312 hom.)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.498

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-63478937-C-G is Benign according to our data. Variant chr17-63478937-C-G is described in ClinVar as [Benign]. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACE	NM_000789.4	c.418-70C>G		intron_variant		ENST00000290866.10	NP_000780.1
ACE	NM_001382700.1	c.182+839C>G		intron_variant			NP_001369629.1
ACE	NM_001382701.1	c.-198+839C>G		intron_variant			NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.418-70C>G		intron_variant		1	NM_000789.4	ENSP00000290866	P1

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93385 AN: 151798 Hom.: 28773 Cov.: 31

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.605

GnomAD4 exome AF: 0.624 AC: 755668 AN: 1210438 Hom.: 236312 Cov.: 17 AF XY: 0.623 AC XY: 379444 AN XY: 609270

Gnomad4 AFR exome AF: 0.583

Gnomad4 AMR exome AF: 0.706

Gnomad4 ASJ exome AF: 0.543

Gnomad4 EAS exome AF: 0.637

Gnomad4 SAS exome AF: 0.626

Gnomad4 FIN exome AF: 0.620

Gnomad4 NFE exome AF: 0.624

Gnomad4 OTH exome AF: 0.620

GnomAD4 genome AF: 0.615 AC: 93469 AN: 151916 Hom.: 28807 Cov.: 31 AF XY: 0.616 AC XY: 45739 AN XY: 74240

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.667

Gnomad4 ASJ AF: 0.555

Gnomad4 EAS AF: 0.646

Gnomad4 SAS AF: 0.627

Gnomad4 FIN AF: 0.615

Gnomad4 NFE AF: 0.620

Gnomad4 OTH AF: 0.600

Alfa AF: 0.617 Hom.: 3596

Bravo AF: 0.615

Asia WGS AF: 0.643 AC: 2235 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.7
DANN	Benign	0.39

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: rs4295; hg19: chr17-61556298;