9-94924026-G-A

Variant names:

• chr9-94924026-G-A
• rs575733167
• NM_001193329.3:c.1405G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001193329.3(AOPEP):​c.1405G>A​(p.Gly469Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000779 in 1,499,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (0 hom.)
• Consequence: AOPEP NM_001193329.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.188
• Publications: 0 publications found

Genes affected

AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

ENSG00000224764 (HGNC:58217):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012637883).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000486 (74/152336) while in subpopulation AMR AF = 0.00118 (18/15302). AF 95% confidence interval is 0.00076. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AOPEP	NM_001193329.3	c.1405G>A	p.Gly469Arg	missense_variant	Exon 6 of 17	ENST00000375315.8	NP_001180258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AOPEP	ENST00000375315.8	c.1405G>A	p.Gly469Arg	missense_variant	Exon 6 of 17	1	NM_001193329.3	ENSP00000364464.2

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.000720

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000518 AC: 58 AN: 112008 AF XY: 0.000478

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000939

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000126

Gnomad NFE exome AF: 0.000836

Gnomad OTH exome AF: 0.00158

GnomAD4 exome AF: 0.000812 AC: 1094 AN: 1347072 Hom.: 0 Cov.: 30 AF XY: 0.000760 AC XY: 504 AN XY: 662804

African (AFR) AF: 0.000102 AC: 3 AN: 29530

American (AMR) AF: 0.00114 AC: 33 AN: 29012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23496

East Asian (EAS) AF: 0.00 AC: 0 AN: 32438

South Asian (SAS) AF: 0.00 AC: 0 AN: 70940

European-Finnish (FIN) AF: 0.0000211 AC: 1 AN: 47302

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5550

European-Non Finnish (NFE) AF: 0.000969 AC: 1020 AN: 1052958

Other (OTH) AF: 0.000645 AC: 36 AN: 55846

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74484

African (AFR) AF: 0.000144 AC: 6 AN: 41586

American (AMR) AF: 0.00118 AC: 18 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000612 Hom.: 0

Bravo AF: 0.000563

ExAC AF: 0.000151 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AOPEP: PM2:Supporting, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.28
DANN	Benign	0.79
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.38	T;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.97	T
PhyloP100		0.19
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.097
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.28	T;T;T
Vest4		0.16
MutPred		0.65		Gain of methylation at G469 (P = 0.0402);Gain of methylation at G469 (P = 0.0402);.;
MVP		0.22
MPC		0.27
ClinPred		0.024	T
GERP RS		-7.2
gMVP		0.30
Mutation Taster		=97/3	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: rs575733167; hg19: chr9-97686308;