Genetic Variant NM_000789.4:c.3692-6G>C (chr17-63497131-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000789.4(ACE):c.3692-6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACE
NM_000789.4 splice_region, intron

Scores

Splicing: ADA: 0.00001969

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.08

Publications

55 publications found

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 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

ACE links:

ENSG00000264813 (HGNC:):

ENSG00000264813 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4 link	c.3692-6G>C		splice_region_variant, intron_variant	Intron 24 of 24	ENST00000290866.10	NP_000780.1	P12821-1B4DKH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10 link	c.3692-6G>C		splice_region_variant, intron_variant	Intron 24 of 24	1	NM_000789.4	ENSP00000290866.4		P12821-1
ENSG00000264813	ENST00000577647.2 link	n.1969+146G>C		intron_variant	Intron 13 of 30	2		ENSP00000464149.1		F6X3S4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151658

Hom.:

Cov.:

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:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1448674

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720668

African (AFR)

AF:

0.00

AC:

AN:

33400

American (AMR)

AF:

0.00

AC:

AN:

43942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25934

East Asian (EAS)

AF:

0.00

AC:

AN:

39520

South Asian (SAS)

AF:

0.00

AC:

AN:

85482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4912

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109844

Other (OTH)

AF:

0.00

AC:

AN:

60050

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151658

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74032

African (AFR)

AF:

0.00

AC:

AN:

41266

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67878

Other (OTH)

AF:

0.00

AC:

AN:

2086

Alfa

AF:

0.00

Hom.:

32043

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.49

(source)

DANN

Benign

0.61

PhyloP100

-1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000020

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over