17-2043033-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000572195.3(OVCA2):​c.613G>A​(p.Gly205Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,028 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000048 ( 1 hom. )

Consequence

OVCA2
ENST00000572195.3 missense

Scores

7
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.31
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OVCA2NM_080822.3 linkuse as main transcriptc.613G>A p.Gly205Ser missense_variant 2/2 ENST00000572195.3 NP_543012.1
DPH1NM_001383.6 linkuse as main transcriptc.*447G>A 3_prime_UTR_variant 13/13 ENST00000263083.12 NP_001374.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OVCA2ENST00000572195.3 linkuse as main transcriptc.613G>A p.Gly205Ser missense_variant 2/21 NM_080822.3 ENSP00000461388 P1
DPH1ENST00000263083.12 linkuse as main transcriptc.*447G>A 3_prime_UTR_variant 13/131 NM_001383.6 ENSP00000263083 P1Q9BZG8-4
ENST00000572404.1 linkuse as main transcriptn.351+42C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00637
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
248840
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134790
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000360
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000479
AC:
70
AN:
1461730
Hom.:
1
Cov.:
32
AF XY:
0.0000495
AC XY:
36
AN XY:
727156
show subpopulations
Gnomad4 AFR exome
AF:
0.000448
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000342
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000133
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 28, 2023The c.613G>A (p.G205S) alteration is located in exon 2 (coding exon 2) of the OVCA2 gene. This alteration results from a G to A substitution at nucleotide position 613, causing the glycine (G) at amino acid position 205 to be replaced by a serine (S). 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
Uncertain
0.51
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
T
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.041
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
-0.076
T
MutationAssessor
Pathogenic
3.2
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.56
T
Sift4G
Pathogenic
0.0
D
Polyphen
0.94
P
Vest4
0.90
MutPred
0.81
Gain of glycosylation at G205 (P = 0.0082);
MVP
0.67
MPC
0.21
ClinPred
0.97
D
GERP RS
4.4
Varity_R
0.61
gMVP
0.69

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs778612638; hg19: chr17-1946327; API