NM_000789.4:c.14C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000789.4(ACE):c.14C>T(p.Ser5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,320,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S5S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Consequence

ACE
NM_000789.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.999

Publications

0 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 - ACE
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
renal tubular dysgenesis of genetic origin
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
intracerebral hemorrhage
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07868388).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000789.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACE	NM_000789.4	MANE Select	c.14C>T	p.Ser5Leu	missense	Exon 1 of 25	NP_000780.1	P12821-1
ACE	NM_001382700.1		c.-222C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 22	NP_001369629.1
ACE	NM_001382701.1		c.-601C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_001369630.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACE	ENST00000290866.10	TSL:1 MANE Select	c.14C>T	p.Ser5Leu	missense	Exon 1 of 25	ENSP00000290866.4	P12821-1
ACE	ENST00000953328.1		c.14C>T	p.Ser5Leu	missense	Exon 1 of 25	ENSP00000623387.1
ACE	ENST00000884279.1		c.14C>T	p.Ser5Leu	missense	Exon 1 of 25	ENSP00000554338.1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151248

Hom.:

Cov.:

show subpopulations

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:

0.000482

GnomAD4 exome

AF:

8.55e-7

AC:

AN:

1169658

Hom.:

Cov.:

AF XY:

0.00000176

AC XY:

AN XY:

568812

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22944

American (AMR)

AF:

0.00

AC:

AN:

8908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15140

East Asian (EAS)

AF:

0.00

AC:

AN:

26070

South Asian (SAS)

AF:

0.00

AC:

AN:

43186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3202

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

975392

Other (OTH)

AF:

0.0000211

AC:

AN:

47464

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151248

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73864

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41194

American (AMR)

AF:

0.00

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67744

Other (OTH)

AF:

0.000482

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.59

M_CAP

Benign

0.084

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.40

REVEL

Benign

0.078

Sift

Benign

0.35

Sift4G

Benign

0.19

Polyphen

0.0010

Vest4

0.24

MutPred

0.14

Loss of phosphorylation at G5 (P = 0.0108)

MVP

0.36

MPC

0.092

ClinPred

0.071

GERP RS

0.56

PromoterAI

0.033

Neutral

(source)

Varity_R

0.035

gMVP

0.31

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over