Genetic Variant GNAL:p.Gly16Arg (chr18-11689609-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_182978.4(GNAL):c.46G>A(p.Gly16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAL
NM_182978.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.83

Publications

0 publications found

Variant links:

Genes affected

GNAL (HGNC:4388): (G protein subunit alpha L) This gene encodes a stimulatory G protein alpha subunit which mediates odorant signaling in the olfactory epithelium. This protein couples dopamine type 1 receptors and adenosine A2A receptors and is widely expressed in the central nervous system. Mutations in this gene have been associated with dystonia 25 and this gene is located in a susceptibility region for bipolar disorder and schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

GNAL Gene-Disease associations (from GenCC):

dystonia 25
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

GNAL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21787548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAL	NM_182978.4 link	c.46G>A	p.Gly16Arg	missense_variant	Exon 1 of 12	ENST00000334049.11	NP_892023.1	P38405-2
GNAL	XM_006722324.4 link	c.46G>A	p.Gly16Arg	missense_variant	Exon 1 of 6		XP_006722387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11 link	c.46G>A	p.Gly16Arg	missense_variant	Exon 1 of 12	1	NM_182978.4	ENSP00000334051.5		P38405-2
GNAL	ENST00000585590.1 link	n.-81G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1191250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

578680

African (AFR)

AF:

0.00

AC:

AN:

23280

American (AMR)

AF:

0.00

AC:

AN:

9220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15940

East Asian (EAS)

AF:

0.00

AC:

AN:

26726

South Asian (SAS)

AF:

0.00

AC:

AN:

46196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3300

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

989700

Other (OTH)

AF:

0.00

AC:

AN:

48648

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.58

PhyloP100

2.8

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.090

REVEL

Benign

0.24

Sift

Benign

0.046

Sift4G

Benign

0.12

Vest4

0.12

MutPred

0.17

Loss of relative solvent accessibility (P = 0.0404);

MVP

0.30

MPC

1.5

ClinPred

0.78

GERP RS

3.4

PromoterAI

-0.018

Neutral

(source)

gMVP

0.14

Mutation Taster

=95/5

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over