16-56192598-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_020988.3(GNAO1):​c.143C>T​(p.Thr48Ile) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 26)

Consequence

GNAO1
NM_020988.3 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 7.69
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 17 ACMG points.

PM1
In a region_of_interest G1 motif (size 13) 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;
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, 0.984
PP5
Variant 16-56192598-C-T is Pathogenic according to our data. Variant chr16-56192598-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNAO1NM_020988.3 linkc.143C>T p.Thr48Ile missense_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.143C>T p.Thr48Ile missense_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: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Mar 14, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.143C>T (p.T48I) alteration is located in exon 2 (coding exon 2) of the GNAO1 gene. This alteration results from a C to T substitution at nucleotide position 143, causing the threonine (T) at amino acid position 48 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with epilepsy, movement disorders, seizures, and other clinical features consistent with GNAO1 encephalopathy (Domínguez-Carral, 2023; Li, 2023). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Apr 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 48 of the GNAO1 protein (p.Thr48Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 435341). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNAO1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy, 17 Pathogenic:1
Jul 05, 2016
Genetic Services Laboratory, University of Chicago
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 17;C4479569:Neurodevelopmental disorder with involuntary movements Other:1
-
GenomeConnect - Brain Gene Registry
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 05-09-2022 by Invitae . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;.;D;.;T;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.95
.;D;D;D;D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.5
H;.;H;H;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-4.8
D;.;.;D;.;.
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;.;.;D;.;.
Sift4G
Pathogenic
0.0
D;.;.;D;D;.
Polyphen
1.0
D;.;D;D;.;.
Vest4
0.94
MutPred
0.89
Loss of disorder (P = 0.0561);Loss of disorder (P = 0.0561);Loss of disorder (P = 0.0561);Loss of disorder (P = 0.0561);Loss of disorder (P = 0.0561);Loss of disorder (P = 0.0561);
MVP
0.97
MPC
2.8
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.95
gMVP
1.0

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: rs1555499800; hg19: chr16-56226510; API