rs4980

Variant names:

• chr17-63497281-G-A
• rs4980
• NM_000789.4:c.3836G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-63497281-G-A
• chr17-63497281-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000789.4(ACE):​c.3836G>A​(p.Arg1279Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 1,557,882 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1279P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (26 hom.)
• Consequence: ACE NM_000789.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.24
• Publications: 26 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066785812).
• BP6: Variant 17-63497281-G-A is Benign according to our data. Variant chr17-63497281-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00528 (804/152260) while in subpopulation NFE AF = 0.007 (476/68004). AF 95% confidence interval is 0.00648. There are 0 homozygotes in GnomAd4. There are 393 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 26 AR,Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	NM_000789.4	MANE Select	c.3836G>A	p.Arg1279Gln	missense	Exon 25 of 25	NP_000780.1
	ACE	NM_001382700.1		c.3269G>A	p.Arg1090Gln	missense	Exon 22 of 22	NP_001369629.1
	ACE	NM_001382701.1		c.2984G>A	p.Arg995Gln	missense	Exon 23 of 23	NP_001369630.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	ENST00000290866.10	TSL:1 MANE Select	c.3836G>A	p.Arg1279Gln	missense	Exon 25 of 25	ENSP00000290866.4
	ACE	ENST00000290863.10	TSL:1	c.2114G>A	p.Arg705Gln	missense	Exon 14 of 14	ENSP00000290863.6
	ENSG00000264813	ENST00000577647.2	TSL:2	n.1969+296G>A		intron	N/A	ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 803 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00700

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00410 AC: 635 AN: 154786 AF XY: 0.00404

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.00658

Gnomad OTH exome AF: 0.00691

GnomAD4 exome AF: 0.00527 AC: 7406 AN: 1405622 Hom.: 26 Cov.: 34 AF XY: 0.00524 AC XY: 3639 AN XY: 694598

African (AFR) AF: 0.00267 AC: 86 AN: 32230

American (AMR) AF: 0.00272 AC: 100 AN: 36718

Ashkenazi Jewish (ASJ) AF: 0.000753 AC: 19 AN: 25216

East Asian (EAS) AF: 0.00 AC: 0 AN: 36860

South Asian (SAS) AF: 0.00216 AC: 173 AN: 80138

European-Finnish (FIN) AF: 0.00751 AC: 348 AN: 46322

Middle Eastern (MID) AF: 0.00981 AC: 46 AN: 4690

European-Non Finnish (NFE) AF: 0.00586 AC: 6354 AN: 1085198

Other (OTH) AF: 0.00481 AC: 280 AN: 58250

GnomAD4 genome AF: 0.00528 AC: 804 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.00528 AC XY: 393 AN XY: 74448

African (AFR) AF: 0.00339 AC: 141 AN: 41552

American (AMR) AF: 0.00484 AC: 74 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00700 AC: 476 AN: 68004

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00530 Hom.: 0

Bravo AF: 0.00493

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00284 AC: 12

ESP6500EA AF: 0.00541 AC: 45

ExAC AF: 0.00312 AC: 352

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Renal tubular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.051
Sift	Benign	0.083	T
Sift4G	Uncertain	0.019	D
Polyphen		0.016	B
Vest4		0.098
MVP		0.74
MPC		0.11
ClinPred		0.010	T
GERP RS		1.4
Varity_R		0.069
gMVP		0.45
Mutation Taster		=83/17	polymorphism

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: rs4980; hg19: chr17-61574642;