16-56192353-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_020988.3(GNAO1):c.118G>T(p.Gly40Trp) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G40A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAO1 NM_020988.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.59

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr16-56192574-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, GNAO1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 16-56192353-G-T is Pathogenic according to our data. Variant chr16-56192353-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 280526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.118G>T	p.Gly40Trp	missense_variant, splice_region_variant	1/9	ENST00000262493.12
GNAO1	NM_138736.3	c.118G>T	p.Gly40Trp	missense_variant, splice_region_variant	1/8
GNAO1	XR_007064866.1	n.865G>T		splice_region_variant, non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.118G>T	p.Gly40Trp	missense_variant, splice_region_variant	1/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1396332 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 698062

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 Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 05, 2020

For these reasons, this variant has been classified as Pathogenic. Different variants affecting this nucleotide (c.118G>C, c.118G>A) have been determined to be pathogenic (PMID: 26485252, 28357411, 28817111). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been observed to be de novo in an individual with early onset epilepsy (PMID: 29390993). ClinVar contains an entry for this variant (Variation ID: 280526). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with tryptophan at codon 40 of the GNAO1 protein (p.Gly40Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. This variant also falls at the last nucleotide of exon 1 of the GNAO1 coding sequence, which is part of the consensus splice site for this exon. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 23, 2018

The G40W pathogenic variant in the GNAO1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, a missense variant at the same residue (G40R) has been reported previously as a pathogenic variant in association with infantile onset epilepsy, developmental delay, and hypotonia (Law et al., 2015). The G40W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G40W variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (G42R) has been reported in the Human Gene Mutation Database in association with early infantile epileptic encephalopathy 17 (Stenson et al., 2014), further supporting the functional importance of this region of the protein. As an alternate mechanism, this variant (c.118 G>T) is also predicted to destroy or damage the natural splice donor site in intron 1, which is expected to cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of c.118 G>T in this individual is unknown. We interpret G40W as a pathogenic variant -

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	35
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.;D;.;D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.5	H;.;H;H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.4	D;.;.;D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;.
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.88
MutPred		0.85		Gain of catalytic residue at L38 (P = 0.0048);Gain of catalytic residue at L38 (P = 0.0048);Gain of catalytic residue at L38 (P = 0.0048);Gain of catalytic residue at L38 (P = 0.0048);Gain of catalytic residue at L38 (P = 0.0048);Gain of catalytic residue at L38 (P = 0.0048);
MVP		0.99
MPC		2.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs886041715; hg19: chr16-56226265;