Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_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. 13/22 in silico tools predict a damaging outcome for this variant. 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. T48N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 26)

Consequence

GNAO1
NM_020988.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.69

Publications

1 publications found

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-DT (HGNC:27543): (GNAO1 divergent transcript)

GNAO1-DT links:

GNAO1-AS1 (HGNC:24498): (GNAO1 antisense RNA 1)

GNAO1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr16-56192598-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 803255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 435341.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.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNAO1	NM_020988.3	MANE Select	c.143C>T	p.Thr48Ile	missense	Exon 2 of 9	NP_066268.1
GNAO1	NM_138736.3		c.143C>T	p.Thr48Ile	missense	Exon 2 of 8	NP_620073.2
GNAO1-AS1	NR_026889.1		n.*19G>A		downstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNAO1	ENST00000262493.12	TSL:1 MANE Select	c.143C>T	p.Thr48Ile	missense	Exon 2 of 9	ENSP00000262493.6
GNAO1	ENST00000262494.13	TSL:1	c.143C>T	p.Thr48Ile	missense	Exon 2 of 8	ENSP00000262494.7
GNAO1	ENST00000638705.1	TSL:1	c.143C>T	p.Thr48Ile	missense	Exon 2 of 8	ENSP00000491223.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy (1)

Developmental and epileptic encephalopathy, 17 (1)

Inborn genetic diseases (1)

Developmental and epileptic encephalopathy, 17;C4479569:Neurodevelopmental disorder with involuntary movements (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

PhyloP100

7.7

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.89

Loss of disorder (P = 0.0561)

MVP

0.97

MPC

2.8

ClinPred

1.0

GERP RS

4.7

PromoterAI

-0.072

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over