NM_001193329.3:c.2017C>T

Variant names:

• chr9-95005197-C-T
• rs1263956569
• NM_001193329.3:c.2017C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001193329.3(AOPEP):​c.2017C>T​(p.Leu673Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,140,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: AOPEP NM_001193329.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.934
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33435678).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193329.3. 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
	AOPEP	NM_001193329.3	MANE Select	c.2017C>T	p.Leu673Phe	missense	Exon 12 of 17	NP_001180258.1	Q8N6M6-1
	AOPEP	NM_001386066.1		c.2017C>T	p.Leu673Phe	missense	Exon 12 of 16	NP_001372995.1
	AOPEP	NM_001386068.1		c.2017C>T	p.Leu673Phe	missense	Exon 13 of 17	NP_001372997.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AOPEP	ENST00000375315.8	TSL:1 MANE Select	c.2017C>T	p.Leu673Phe	missense	Exon 12 of 17	ENSP00000364464.2	Q8N6M6-1
	AOPEP	ENST00000297979.9	TSL:1	c.1720C>T	p.Leu574Phe	missense	Exon 10 of 15	ENSP00000297979.5	Q8N6M6-2
	AOPEP	ENST00000951986.1		c.2017C>T	p.Leu673Phe	missense	Exon 12 of 17	ENSP00000622045.1

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 148274 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000487

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: 0.00

GnomAD4 exome AF: 0.00000101 AC: 1 AN: 992598 Hom.: 0 Cov.: 28 AF XY: 0.00000211 AC XY: 1 AN XY: 473850

African (AFR) AF: 0.00 AC: 0 AN: 19730

American (AMR) AF: 0.00 AC: 0 AN: 11030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9328

East Asian (EAS) AF: 0.00 AC: 0 AN: 15358

South Asian (SAS) AF: 0.00 AC: 0 AN: 23868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2254

European-Non Finnish (NFE) AF: 0.00000116 AC: 1 AN: 861500

Other (OTH) AF: 0.00 AC: 0 AN: 35546

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 148384 Hom.: 0 Cov.: 31 AF XY: 0.0000277 AC XY: 2 AN XY: 72324

African (AFR) AF: 0.0000486 AC: 2 AN: 41186

American (AMR) AF: 0.00 AC: 0 AN: 14946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66476

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.57	T
PhyloP100		0.93
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.087
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.028	D
Vest4		0.46
MutPred		0.61		Loss of sheet (P = 0.0457)
MVP		0.69
MPC		0.25
ClinPred		0.19	T
GERP RS		2.5
PromoterAI		-0.19	Neutral
gMVP		0.38
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: rs1263956569; hg19: chr9-97767479;