rs12720744

Positions:

chr17-63496990-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000789.4(ACE):c.3691+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,606,582 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 30 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 71 hom. )

Consequence

ACE
NM_000789.4 splice_region, intron

Scores

Splicing: ADA: 0.00003931

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.942

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:

ENSG00000264813 (HGNC:):

ENSG00000264813 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 17-63496990-C-T is Benign according to our data. Variant chr17-63496990-C-T is described in ClinVar as [Benign]. Clinvar id is 256805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2181/152092) while in subpopulation AFR AF= 0.036 (1489/41370). AF 95% confidence interval is 0.0345. There are 30 homozygotes in gnomad4. There are 1065 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACE	NM_000789.4 linkuse as main transcript	c.3691+5C>T		splice_region_variant, intron_variant		ENST00000290866.10	NP_000780.1	P12821-1B4DKH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10 linkuse as main transcript	c.3691+5C>T		splice_region_variant, intron_variant		1	NM_000789.4	ENSP00000290866.4		P12821-1
ENSG00000264813	ENST00000577647.2 linkuse as main transcript	n.1969+5C>T		splice_region_variant, intron_variant		2		ENSP00000464149.1		F6X3S4

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2179

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0360

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.00435

Gnomad OTH

AF:

0.0225

GnomAD3 exomes

AF:

0.00746

AC:

1752

AN:

234768

Hom.:

AF XY:

0.00699

AC XY:

893

AN XY:

127782

show subpopulations

Gnomad AFR exome

AF:

0.0335

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0190

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00265

Gnomad FIN exome

AF:

0.00100

Gnomad NFE exome

AF:

0.00497

Gnomad OTH exome

AF:

0.0167

GnomAD4 exome

AF:

0.00544

AC:

7915

AN:

1454490

Hom.:

Cov.:

AF XY:

0.00550

AC XY:

3978

AN XY:

723130

show subpopulations

Gnomad4 AFR exome

AF:

0.0376

Gnomad4 AMR exome

AF:

0.0111

Gnomad4 ASJ exome

AF:

0.0205

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00272

Gnomad4 FIN exome

AF:

0.000820

Gnomad4 NFE exome

AF:

0.00404

Gnomad4 OTH exome

AF:

0.0120

GnomAD4 genome

AF:

0.0143

AC:

2181

AN:

152092

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1065

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0360

Gnomad4 AMR

AF:

0.0160

Gnomad4 ASJ

AF:

0.0184

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00434

Gnomad4 OTH

AF:

0.0222

Alfa

AF:

0.00981

Hom.:

Bravo

AF:

0.0165

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Renal tubular dysgenesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.1

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000039

dbscSNV1_RF

Benign

0.018

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

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