9-94760091-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001193329.3(AOPEP):c.308G>A(p.Ser103Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,146 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (41 hom.)
• Consequence: AOPEP NM_001193329.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.651

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032122731).
• BP6: Variant 9-94760091-G-A is Benign according to our data. Variant chr9-94760091-G-A is described in ClinVar as [Benign]. Clinvar id is 769754.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00158 (241/152262) while in subpopulation EAS AF= 0.017 (88/5188). AF 95% confidence interval is 0.0141. There are 3 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AOPEP	NM_001193329.3	c.308G>A	p.Ser103Asn	missense_variant	2/17	ENST00000375315.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AOPEP	ENST00000375315.8	c.308G>A	p.Ser103Asn	missense_variant	2/17	1	NM_001193329.3	P1
AOPEP	ENST00000297979.9	c.308G>A	p.Ser103Asn	missense_variant	2/15	1
AOPEP	ENST00000277198.6	c.308G>A	p.Ser103Asn	missense_variant	2/8	2
AOPEP	ENST00000489318.2	n.591G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152144 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00878

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00400 AC: 1004 AN: 251234 Hom.: 11 AF XY: 0.00326 AC XY: 442 AN XY: 135764

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0117

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00166 AC: 2425 AN: 1461884 Hom.: 41 Cov.: 31 AF XY: 0.00152 AC XY: 1105 AN XY: 727248

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0352

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152262 Hom.: 3 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74434

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00896

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000876 Hom.: 4

Bravo AF: 0.00249

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00347 AC: 421

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 25, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	17
Dann	Benign	0.97
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.99	N;N;N
PROVEAN	Benign	-0.19	N;N;N
REVEL	Benign	0.043
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.20	T;T;T
Vest4		0.070
MVP		0.33
MPC		0.22
ClinPred		0.0064	T
GERP RS		2.1
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs118018100; hg19: chr9-97522373;