18-11689609-G-A

Variant names:

• chr18-11689609-G-A
• rs1009777479
• NM_182978.4:c.46G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. 12/19 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182978.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	NM_182978.4	MANE Select	c.46G>A	p.Gly16Arg	missense	Exon 1 of 12	NP_892023.1	P38405-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	ENST00000334049.11	TSL:1 MANE Select	c.46G>A	p.Gly16Arg	missense	Exon 1 of 12	ENSP00000334051.5	P38405-2
	GNAL	ENST00000585590.1	TSL:2	n.-81G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1191250 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 578680

African (AFR) AF: 0.00 AC: 0 AN: 23280

American (AMR) AF: 0.00 AC: 0 AN: 9220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15940

East Asian (EAS) AF: 0.00 AC: 0 AN: 26726

South Asian (SAS) AF: 0.00 AC: 0 AN: 46196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 989700

Other (OTH) AF: 0.00 AC: 0 AN: 48648

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.58	T
PhyloP100		2.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.090	N
REVEL	Benign	0.24
Sift	Benign	0.046	D
Sift4G	Benign	0.12	T
Vest4		0.12
MutPred		0.17		Loss of relative solvent accessibility (P = 0.0404)
MVP		0.30
MPC		1.5
ClinPred		0.78	D
GERP RS		3.4
PromoterAI		-0.018	Neutral
gMVP		0.14
Mutation Taster		=95/5	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1009777479; hg19: chr18-11689608;