chr18-11700535-A-G

Variant names:

• chr18-11700535-A-G
• rs1013459
• NM_182978.4:c.376+10596A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182978.4(GNAL):​c.376+10596A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 152,216 control chromosomes in the GnomAD database, including 10,332 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (10332 hom., cov: 32)
• Consequence: GNAL NM_182978.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.807
• Publications: 10 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAL	NM_182978.4	c.376+10596A>G		intron_variant	Intron 1 of 11	ENST00000334049.11	NP_892023.1
GNAL	XM_006722324.4	c.376+10596A>G		intron_variant	Intron 1 of 5		XP_006722387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11	c.376+10596A>G		intron_variant	Intron 1 of 11	1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000585590.1	n.251-1536A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42103 AN: 152098 Hom.: 10291 Cov.: 32

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.0226

Gnomad SAS AF: 0.0857

Gnomad FIN AF: 0.0788

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.249

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.277 AC: 42191 AN: 152216 Hom.: 10332 Cov.: 32 AF XY: 0.269 AC XY: 20045 AN XY: 74440

African (AFR) AF: 0.664 AC: 27559 AN: 41488

American (AMR) AF: 0.151 AC: 2316 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3472

East Asian (EAS) AF: 0.0224 AC: 116 AN: 5176

South Asian (SAS) AF: 0.0847 AC: 409 AN: 4826

European-Finnish (FIN) AF: 0.0788 AC: 838 AN: 10628

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9493 AN: 68010

Other (OTH) AF: 0.247 AC: 522 AN: 2114

Alfa AF: 0.174 Hom.: 7957

Bravo AF: 0.299

Asia WGS AF: 0.0920 AC: 321 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.5
DANN	Benign	0.65
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1013459; hg19: chr18-11700534;