rs1019446111

Variant names:

• chr9-94928479-C-A
• rs1019446111
• NM_001193329.3:c.1609C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-94928479-C-A
• chr9-94928479-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001193329.3(AOPEP):​c.1609C>A​(p.Arg537Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,146 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R537C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: AOPEP NM_001193329.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.633
• 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]

AOPEP-AS1 (HGNC:58217):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19389606).

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.1609C>A	p.Arg537Ser	missense	Exon 7 of 17	NP_001180258.1	Q8N6M6-1
	AOPEP	NM_001386066.1		c.1609C>A	p.Arg537Ser	missense	Exon 7 of 16	NP_001372995.1
	AOPEP	NM_001386068.1		c.1609C>A	p.Arg537Ser	missense	Exon 8 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.1609C>A	p.Arg537Ser	missense	Exon 7 of 17	ENSP00000364464.2	Q8N6M6-1
	AOPEP	ENST00000297979.9	TSL:1	c.1365-26698C>A		intron	N/A	ENSP00000297979.5	Q8N6M6-2
	AOPEP	ENST00000951986.1		c.1609C>A	p.Arg537Ser	missense	Exon 7 of 17	ENSP00000622045.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 150042 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398146 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 689616

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079000

Other (OTH) AF: 0.00 AC: 0 AN: 58072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.63
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.062
Sift	Benign	0.23	T
Sift4G	Benign	0.10	T
Vest4		0.33
MutPred		0.39		Gain of phosphorylation at R537 (P = 0.0444)
MVP		0.25
MPC		0.76
ClinPred		0.95	D
GERP RS		3.3
gMVP		0.40
Mutation Taster		=71/29	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: rs1019446111; hg19: chr9-97690761;