17-2042979-A-T
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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
NM_080822.3 missense
Scores
4
8
4
Clinical Significance
Conservation
PhyloP100: 5.93
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 |
---|---|---|---|---|---|---|---|---|
OVCA2 | NM_080822.3 | c.559A>T | p.Ser187Cys | missense_variant | 2/2 | ENST00000572195.3 | NP_543012.1 | |
DPH1 | NM_001383.6 | c.*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 |
---|---|---|---|---|---|---|---|---|---|---|
OVCA2 | ENST00000572195.3 | c.559A>T | p.Ser187Cys | missense_variant | 2/2 | 1 | NM_080822.3 | ENSP00000461388 | P1 | |
DPH1 | ENST00000263083.12 | c.*393A>T | 3_prime_UTR_variant | 13/13 | 1 | NM_001383.6 | ENSP00000263083 | P1 | ||
ENST00000572404.1 | n.352-9T>A | splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 248956Hom.: 0 AF XY: 0.0000445 AC XY: 6AN XY: 134808
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GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461798Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727184
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GnomAD4 genome Cov.: 32
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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 submitter | clinical testing | Ambry Genetics | Aug 03, 2022 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of disorder (P = 0.0049);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at