rs758424351

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_020988.3(GNAO1):c.425A>C(p.Asn142Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAO1
NM_020988.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.28

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 links:

GNAO1 (HGNC:):

GNAO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNAO1. . Gene score misZ 3.1919 (greater than the threshold 3.09). Trascript score misZ 4.549 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 17, neurodevelopmental disorder with involuntary movements, developmental and epileptic encephalopathy, movement disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.40278596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAO1	NM_020988.3 linkuse as main transcript	c.425A>C	p.Asn142Thr	missense_variant	4/9	ENST00000262493.12	NP_066268.1	P09471-1Q8N6I9B3KP89
GNAO1	NM_138736.3 linkuse as main transcript	c.425A>C	p.Asn142Thr	missense_variant	4/8		NP_620073.2	P09471-2Q8N6I9B3KP89Q6AWC5
GNAO1	XM_011523003.4 linkuse as main transcript	c.299A>C	p.Asn100Thr	missense_variant	4/9		XP_011521305.1
GNAO1	XR_007064866.1 linkuse as main transcript	n.1172A>C		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12 linkuse as main transcript	c.425A>C	p.Asn142Thr	missense_variant	4/9	1	NM_020988.3	ENSP00000262493.6		P09471-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461574

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727102

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt GNAO1 protein function. This variant has not been reported in the literature in individuals affected with GNAO1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 142 of the GNAO1 protein (p.Asn142Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.0024

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

T;T;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

0.0069

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

.;D;D;D

M_CAP

Benign

0.078

MetaRNN

Benign

0.40

T;T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.0

L;L;L;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.1

N;.;N;.

REVEL

Benign

0.19

Sift

Benign

0.27

T;.;T;.

Sift4G

Benign

0.21

T;.;T;.

Polyphen

0.0050

B;B;B;.

Vest4

0.36

MutPred

0.31

Gain of phosphorylation at N142 (P = 0.0604);Gain of phosphorylation at N142 (P = 0.0604);Gain of phosphorylation at N142 (P = 0.0604);.;

MVP

0.66

MPC

1.5

ClinPred

0.84

GERP RS

5.0

Varity_R

0.26

gMVP

0.76

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over