rs4646140

Variant names:

• chrX-15587729-C-T
• rs4646140
• NM_001371415.1:c.802+24G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001371415.1(ACE2):​c.802+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,077,075 control chromosomes in the GnomAD database, including 389 homozygotes. There are 3,655 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (181 hom., 1153 hem., cov: 23)
  • Exomes 𝑓: 0.0076 (208 hom. 2502 hem.)
• Consequence: ACE2 NM_001371415.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 17 publications found

Genes affected

ACE2 (HGNC:13557): (angiotensin converting enzyme 2) The protein encoded by this gene belongs to the angiotensin-converting enzyme family of dipeptidyl carboxydipeptidases and has considerable homology to human angiotensin 1 converting enzyme. This secreted protein catalyzes the cleavage of angiotensin I into angiotensin 1-9, and angiotensin II into the vasodilator angiotensin 1-7. ACE2 is known to be expressed in various human organs, and its organ- and cell-specific expression suggests that it may play a role in the regulation of cardiovascular and renal function, as well as fertility. In addition, the encoded protein is a functional receptor for the spike glycoprotein of the human coronavirus HCoV-NL63 and the human severe acute respiratory syndrome coronaviruses, SARS-CoV and SARS-CoV-2, the latter is the causative agent of coronavirus disease-2019 (COVID-19). Multiple splice variants have been found for this gene and the dACE2 (or MIRb-ACE2) splice variant has been found to be interferon inducible. [provided by RefSeq, Nov 2020]

ENSG00000285602 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE2	NM_001371415.1	c.802+24G>A		intron_variant	Intron 6 of 17	ENST00000252519.8	NP_001358344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE2	ENST00000252519.8	c.802+24G>A		intron_variant	Intron 6 of 17	1	NM_001371415.1	ENSP00000252519.3
ENSG00000285602	ENST00000649243.1	n.*880+24G>A		intron_variant	Intron 11 of 19			ENSP00000497489.1

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 4058 AN: 111556 Hom.: 181 Cov.: 23

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0297

Gnomad SAS AF: 0.0607

Gnomad FIN AF: 0.000167

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.0304

GnomAD2 exomes AF: 0.0180 AC: 2680 AN: 149031 AF XY: 0.0166

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.00753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0246

Gnomad FIN exome AF: 0.000395

Gnomad NFE exome AF: 0.000442

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00759 AC: 7331 AN: 965468 Hom.: 208 Cov.: 15 AF XY: 0.00914 AC XY: 2502 AN XY: 273608

African (AFR) AF: 0.120 AC: 2737 AN: 22858

American (AMR) AF: 0.00912 AC: 261 AN: 28606

Ashkenazi Jewish (ASJ) AF: 0.0000577 AC: 1 AN: 17331

East Asian (EAS) AF: 0.0347 AC: 967 AN: 27843

South Asian (SAS) AF: 0.0579 AC: 2442 AN: 42169

European-Finnish (FIN) AF: 0.000254 AC: 10 AN: 39381

Middle Eastern (MID) AF: 0.0138 AC: 52 AN: 3775

European-Non Finnish (NFE) AF: 0.000361 AC: 268 AN: 742167

Other (OTH) AF: 0.0143 AC: 593 AN: 41338

GnomAD4 genome AF: 0.0363 AC: 4055 AN: 111607 Hom.: 181 Cov.: 23 AF XY: 0.0341 AC XY: 1153 AN XY: 33817

African (AFR) AF: 0.117 AC: 3582 AN: 30633

American (AMR) AF: 0.0127 AC: 133 AN: 10499

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.0295 AC: 105 AN: 3558

South Asian (SAS) AF: 0.0613 AC: 166 AN: 2709

European-Finnish (FIN) AF: 0.000167 AC: 1 AN: 5985

Middle Eastern (MID) AF: 0.0184 AC: 4 AN: 217

European-Non Finnish (NFE) AF: 0.000339 AC: 18 AN: 53155

Other (OTH) AF: 0.0301 AC: 46 AN: 1530

Alfa AF: 0.00938 Hom.: 287

Bravo AF: 0.0400

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.71
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs4646140; hg19: chrX-15605852;