chr17-2042979-A-T

Variant summary

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

The NM_080822.3(OVCA2):​c.559A>T​(p.Ser187Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

OVCA2
NM_080822.3 missense

Scores

4
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.93
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]

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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, 0.971

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OVCA2NM_080822.3 linkuse as main transcriptc.559A>T p.Ser187Cys missense_variant 2/2 ENST00000572195.3 NP_543012.1
DPH1NM_001383.6 linkuse as main transcriptc.*393A>T 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.559A>T p.Ser187Cys missense_variant 2/21 NM_080822.3 ENSP00000461388 P1
DPH1ENST00000263083.12 linkuse as main transcriptc.*393A>T 3_prime_UTR_variant 13/131 NM_001383.6 ENSP00000263083 P1Q9BZG8-4
ENST00000572404.1 linkuse as main transcriptn.352-9T>A splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000281
AC:
7
AN:
248956
Hom.:
0
AF XY:
0.0000445
AC XY:
6
AN XY:
134808
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:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000270
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000198
AC:
29
AN:
1461798
Hom.:
0
Cov.:
32
AF XY:
0.0000303
AC XY:
22
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000174
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

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 GeneticsAug 03, 2022The c.559A>T (p.S187C) alteration is located in exon 2 (coding exon 2) of the OVCA2 gene. This alteration results from a A to T substitution at nucleotide position 559, causing the serine (S) at amino acid position 187 to be replaced by a cysteine (C). 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
0.37
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.34
T
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.58
T
M_CAP
Benign
0.069
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
-0.071
T
MutationAssessor
Pathogenic
3.0
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.48
T
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.70
MutPred
0.82
Loss of disorder (P = 0.0049);
MVP
0.53
MPC
0.20
ClinPred
0.96
D
GERP RS
5.4
Varity_R
0.51
gMVP
0.57

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

LitVar

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

Other links and lift over

dbSNP: rs771958531; hg19: chr17-1946273; API