Genetic Variant OVCA2:p.Leu7Met (chr17-2042066-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080822.3(OVCA2):c.19C>A(p.Leu7Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,552,708 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

OVCA2
NM_080822.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.224

Variant links:

Genes affected

OVCA2 (HGNC:24203): (OVCA2 serine hydrolase domain containing) Involved in response to retinoic acid. Located in cytoplasm. Biomarker of ovarian cancer. [provided by Alliance of Genome Resources, Apr 2022]

OVCA2 links:

DPH1 (HGNC:3003): (diphthamide biosynthesis 1) The protein encoded by this gene is an enzyme involved in the biosynthesis of diphthamide, a modified histidine found only in elongation factor-2 (EEF2). Diphthamide residues in EEF2 are targeted for ADP-ribosylation by diphtheria toxin and Pseudomonas exotoxin A. Defects in this gene have been associated with both ovarian cancer and autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies. [provided by RefSeq, Oct 2016]

DPH1 links:

ENSG00000287553 (HGNC:):

ENSG00000287553 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
OVCA2	NM_080822.3 link	c.19C>A	p.Leu7Met	missense_variant	Exon 1 of 2	ENST00000572195.3	NP_543012.1	Q8WZ82
DPH1	NM_001383.6 link	c.*18+191C>A		intron_variant	Intron 12 of 12	ENST00000263083.12	NP_001374.4	Q9BZG8-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OVCA2	ENST00000572195.3 link	c.19C>A	p.Leu7Met	missense_variant	Exon 1 of 2	1	NM_080822.3	ENSP00000461388.1		Q8WZ82
DPH1	ENST00000263083.12 link	c.*18+191C>A		intron_variant	Intron 12 of 12	1	NM_001383.6	ENSP00000263083.7		Q9BZG8-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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:

7.14e-7

AC:

AN:

1400378

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000272

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

0.0018

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.061

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.50

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.66

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.76

Sift4G

Benign

0.093

Polyphen

1.0

Vest4

0.50

MutPred

0.79

Gain of catalytic residue at L7 (P = 0.0199);

MVP

0.33

MPC

0.20

ClinPred

0.92

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.080

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over