rs754444042

Variant names:

• chr9-94800839-C-T
• rs754444042
• NM_001193329.3:c.1201C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001193329.3(AOPEP):​c.1201C>T​(p.Arg401Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: AOPEP NM_001193329.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26
• Publications: 2 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]

LOC124902220 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AOPEP	NM_001193329.3	c.1201C>T	p.Arg401Trp	missense_variant	Exon 5 of 17	ENST00000375315.8	NP_001180258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AOPEP	ENST00000375315.8	c.1201C>T	p.Arg401Trp	missense_variant	Exon 5 of 17	1	NM_001193329.3	ENSP00000364464.2
AOPEP	ENST00000297979.9	c.1201C>T	p.Arg401Trp	missense_variant	Exon 5 of 15	1		ENSP00000297979.5
AOPEP	ENST00000277198.6	c.1201C>T	p.Arg401Trp	missense_variant	Exon 5 of 8	2		ENSP00000277198.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251406 AF XY: 0.0000662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111998

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 31 Uncertain:1

Sep 18, 2023

Department of Medical Genetics and Molecular Medicine, Mashhad University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The AOPEP variant (c.1201C>T) is classified as VUS based on: Phenotype match: The patient's generalized dystonia aligns with AOPEP-associated disorders dystonia 31. The variant is extremely rare (>0.005) in population databases (gnomAD). In silico predictions: Computational tools (SIFT, PolyPhen-2, MutationTaster) predict a deleterious effect on protein function. Functional impact: The variant affects a conserved residue in a critical protein domain (e.g., zinc-binding site), predicted to disrupt function. ACMG criteria: Applied criteria include PM2 due to loss-of-function effect, rar in controls. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-1.2	T
PhyloP100		2.3
PROVEAN	Pathogenic	-5.1	D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.93
MVP		0.61
MPC		0.86
ClinPred		0.87	D
GERP RS		4.2
gMVP		0.87
Mutation Taster		=72/28	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: rs754444042; hg19: chr9-97563121;