chr18-11689523-T-C

Position:

• chr18-11689523-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182978.4(GNAL):​c.-41T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,033,504 control chromosomes in the GnomAD database, including 41,303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (12875 hom., cov: 33)
  • Exomes 𝑓: 0.24 (28428 hom.)
• Consequence: GNAL NM_182978.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.774

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 18-11689523-T-C is Benign according to our data. Variant chr18-11689523-T-C is described in ClinVar as [Benign]. Clinvar id is 1246973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAL	NM_182978.4	c.-41T>C		5_prime_UTR_variant	1/12	ENST00000334049.11
GNAL	XM_006722324.4	c.-41T>C		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAL	ENST00000334049.11	c.-41T>C		5_prime_UTR_variant	1/12	1	NM_182978.4

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53023 AN: 151806 Hom.: 12838 Cov.: 33

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.258 AC: 82 AN: 318 Hom.: 12 AF XY: 0.308 AC XY: 56 AN XY: 182

Gnomad SAS exome AF: 0.500

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.238 AC: 209505 AN: 881590 Hom.: 28428 Cov.: 12 AF XY: 0.237 AC XY: 99977 AN XY: 422180

Gnomad4 AFR exome AF: 0.706

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.0330

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.350 AC: 53101 AN: 151914 Hom.: 12875 Cov.: 33 AF XY: 0.341 AC XY: 25321 AN XY: 74294

Gnomad4 AFR AF: 0.691

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.283

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.330

Alfa AF: 0.123 Hom.: 198

Bravo AF: 0.367

Asia WGS AF: 0.116 AC: 399 AN: 3418

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 31, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 24. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Dystonia 25 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9303742; hg19: chr18-11689522;