18-11689815-G-A

Position:

• chr18-11689815-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_182978.4(GNAL):​c.252G>A​(p.Glu84Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,537,772 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: GNAL NM_182978.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.28

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 18-11689815-G-A is Benign according to our data. Variant chr18-11689815-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1175112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-11689815-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00181 (275/152088) while in subpopulation AMR AF= 0.00347 (53/15276). AF 95% confidence interval is 0.00272. There are 0 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 275 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAL	NM_182978.4	c.252G>A	p.Glu84Glu	synonymous_variant	1/12	ENST00000334049.11	NP_892023.1
GNAL	XM_006722324.4	c.252G>A	p.Glu84Glu	synonymous_variant	1/6		XP_006722387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11	c.252G>A	p.Glu84Glu	synonymous_variant	1/12	1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000585590.1	n.126G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 151980 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00179 AC: 253 AN: 141000 Hom.: 1 AF XY: 0.00201 AC XY: 158 AN XY: 78484

Gnomad AFR exome AF: 0.000414

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.000901

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00308

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00161

GnomAD4 exome AF: 0.00243 AC: 3364 AN: 1385684 Hom.: 9 Cov.: 32 AF XY: 0.00245 AC XY: 1679 AN XY: 685442

Gnomad4 AFR exome AF: 0.000309

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.000774

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00326

Gnomad4 FIN exome AF: 0.000136

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00181 AC: 275 AN: 152088 Hom.: 0 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74358

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00260

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00195 Hom.: 2

Bravo AF: 0.00181

Asia WGS AF: 0.00146 AC: 5 AN: 3430

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	GNAL: BP4, BP7, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

GNAL-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Uncertain	0.98

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs370118361; hg19: chr18-11689814; COSMIC: COSV61849190;