16-56192326-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_020988.3(GNAO1):c.91G>T(p.Ala31Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAO1 NM_020988.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.53

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_020988.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GNAO1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAO1	NM_020988.3	c.91G>T	p.Ala31Ser	missense_variant	1/9	ENST00000262493.12
GNAO1	NM_138736.3	c.91G>T	p.Ala31Ser	missense_variant	1/8
GNAO1	XR_007064866.1	n.838G>T		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAO1	ENST00000262493.12	c.91G>T	p.Ala31Ser	missense_variant	1/9	1	NM_020988.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2017

The p.A31S variant (also known as c.91G>T), located in coding exon 1 of the GNAO1 gene, results from a G to T substitution at nucleotide position 91. The alanine at codon 31 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;T;.;T;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.1	L;.;L;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.88	N;.;.;N;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.088	T;.;.;T;.;.
Sift4G	Benign	0.57	T;.;.;T;T;.
Polyphen		0.18	B;.;B;B;.;.
Vest4		0.48
MutPred		0.32		Gain of disorder (P = 0.0417);Gain of disorder (P = 0.0417);Gain of disorder (P = 0.0417);Gain of disorder (P = 0.0417);Gain of disorder (P = 0.0417);Gain of disorder (P = 0.0417);
MVP		0.76
MPC		2.1
ClinPred		0.90	D
GERP RS		4.8
Varity_R		0.58
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-56226238;