9-94955271-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001193329.3(AOPEP):c.1756T>C(p.Tyr586His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AOPEP NM_001193329.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a site Transition state stabilizer (size 0) in uniprot entity AMPO_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AOPEP	NM_001193329.3	c.1756T>C	p.Tyr586His	missense_variant	8/17	ENST00000375315.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AOPEP	ENST00000375315.8	c.1756T>C	p.Tyr586His	missense_variant	8/17	1	NM_001193329.3	P1
AOPEP	ENST00000297979.9	c.1459T>C	p.Tyr487His	missense_variant	6/15	1
AOPEP	ENST00000462125.5	n.422T>C		non_coding_transcript_exon_variant	3/10	3
AOPEP	ENST00000479161.5	n.478T>C		non_coding_transcript_exon_variant	4/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The c.1756T>C (p.Y586H) alteration is located in exon 7 (coding exon 7) of the C9orf3 gene. This alteration results from a T to C substitution at nucleotide position 1756, causing the tyrosine (Y) at amino acid position 586 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;T;D;T
Sift4G	Benign	0.13	T;T;T;T
Vest4		0.94
MutPred		0.71		.;Loss of catalytic residue at Y586 (P = 0.087);.;.;
MVP		0.55
MPC		0.96
ClinPred		1.0	D
GERP RS		5.0
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-97717553;