9-94924026-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 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. 12/18 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AOPEP	NM_001193329.3	c.1405G>A	p.Gly469Arg	missense_variant	6/17	ENST00000375315.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AOPEP	ENST00000375315.8	c.1405G>A	p.Gly469Arg	missense_variant	6/17	1	NM_001193329.3	P1

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

GnomAD3 exomes AF: 0.000518 AC: 58 AN: 112008 Hom.: 0 AF XY: 0.000478 AC XY: 29 AN XY: 60624

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 SAS 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

Gnomad4 AFR exome AF: 0.000102

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000211

Gnomad4 NFE exome AF: 0.000969

Gnomad4 OTH exome AF: 0.000645

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

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.000473

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

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

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
MutationTaster	Benign	1.0	N;N;N;N
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

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

LitVar

Other links and lift over

dbSNP: rs575733167; hg19: chr9-97686308;