rs587777057
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_020988.3(GNAO1):c.607G>A(p.Gly203Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G203E) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
GNAO1
NM_020988.3 missense
NM_020988.3 missense
Scores
17
1
Clinical Significance
Conservation
PhyloP100: 9.99
Publications
54 publications found
Genes affected
GNAO1 (HGNC:4389): (G protein subunit alpha o1) The protein encoded by this gene represents the alpha subunit of the Go heterotrimeric G-protein signal-transducing complex. Defects in this gene are a cause of early-onset epileptic encephalopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]
GNAO1 Gene-Disease associations (from GenCC):
- developmental and epileptic encephalopathy, 17Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
- genetic developmental and epileptic encephalopathyInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- movement disorderInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
- neurodevelopmental disorder with involuntary movementsInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 22 ACMG points.
PS1
Transcript NM_020988.3 (GNAO1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
PM1
In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_020988.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-56336745-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1319183.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 16-56336744-G-A is Pathogenic according to our data. Variant chr16-56336744-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 66115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_020988.3. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GNAO1 | TSL:1 MANE Select | c.607G>A | p.Gly203Arg | missense | Exon 6 of 9 | ENSP00000262493.6 | P09471-1 | ||
| GNAO1 | TSL:1 | c.607G>A | p.Gly203Arg | missense | Exon 6 of 8 | ENSP00000262494.7 | P09471-2 | ||
| GNAO1 | TSL:1 | c.607G>A | p.Gly203Arg | missense | Exon 6 of 8 | ENSP00000491223.1 | P09471-1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1459738Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726098
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1459738
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
726098
African (AFR)
AF:
AC:
0
AN:
33464
American (AMR)
AF:
AC:
0
AN:
44564
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26120
East Asian (EAS)
AF:
AC:
0
AN:
39610
South Asian (SAS)
AF:
AC:
0
AN:
86006
European-Finnish (FIN)
AF:
AC:
0
AN:
52464
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111426
Other (OTH)
AF:
AC:
0
AN:
60322
GnomAD4 genome
GnomAD4 genome
Cov.:
34
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
6
-
-
Developmental and epileptic encephalopathy, 17 (6)
3
-
-
not provided (3)
2
-
-
Developmental and epileptic encephalopathy, 17;C4479569:Neurodevelopmental disorder with involuntary movements (2)
1
-
-
Abnormality of the nervous system (1)
1
-
-
Developmental and epileptic encephalopathy (1)
1
-
-
GNAO1-related disorder (1)
1
-
-
Microcephaly (1)
1
-
-
Rare genetic intellectual disability (1)
-
-
-
GNAO1-Related Neurodevelopmental Disorder (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0199)
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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