16-56192574-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_020988.3(GNAO1):​c.119G>T​(p.Gly40Val) variant causes a missense, splice region 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. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G40R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 26)

Consequence

GNAO1
NM_020988.3 missense, splice_region

Scores

17
1
1
Splicing: ADA: 0.9996
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.60
Variant links:
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-AS1 (HGNC:24498): (GNAO1 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a binding_site (size 7) in uniprot entity GNAO_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr16-56192353-G-C is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in the GNAO1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 70 curated pathogenic missense variants (we use a threshold of 10). The gene has 43 curated benign missense variants. Gene score misZ: 3.1919 (above the threshold of 3.09). Trascript score misZ: 4.549 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 17, neurodevelopmental disorder with involuntary movements, developmental and epileptic encephalopathy, movement disorder.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 16-56192574-G-T is Pathogenic according to our data. Variant chr16-56192574-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 587482.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNAO1NM_020988.3 linkc.119G>T p.Gly40Val missense_variant, splice_region_variant Exon 2 of 9 ENST00000262493.12 NP_066268.1 P09471-1Q8N6I9B3KP89

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNAO1ENST00000262493.12 linkc.119G>T p.Gly40Val missense_variant, splice_region_variant Exon 2 of 9 1 NM_020988.3 ENSP00000262493.6 P09471-1

Frequencies

GnomAD3 genomes
Cov.:
26
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
26

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 1 Pathogenic:1
Aug 07, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Neurodevelopmental disorder with involuntary movements Pathogenic:1
Aug 07, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;.;D;.;D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D;D
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.5
H;.;H;H;.;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.1
D;.;.;D;.;.
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;.;.;D;.;.
Sift4G
Pathogenic
0.0
D;.;.;D;D;.
Polyphen
1.0
D;.;D;D;.;.
Vest4
0.95
MutPred
0.95
Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP
0.98
MPC
2.4
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.98
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
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

LitVar

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

Other links and lift over

dbSNP: rs886041766; hg19: chr16-56226486; API