18-11689700-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182978.4(GNAL):c.137G>A(p.Arg46Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,472,928 control chromosomes in the GnomAD database, including 16,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1276 hom., cov: 33)
  • Exomes 𝑓: 0.15 (14996 hom.)
• Consequence: GNAL NM_182978.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0150

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015120506).
• BP6: Variant 18-11689700-G-A is Benign according to our data. Variant chr18-11689700-G-A is described in ClinVar as [Benign]. Clinvar id is 1169620.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAL	NM_182978.4	c.137G>A	p.Arg46Lys	missense_variant	1/12	ENST00000334049.11
GNAL	XM_006722324.4	c.137G>A	p.Arg46Lys	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAL	ENST00000334049.11	c.137G>A	p.Arg46Lys	missense_variant	1/12	1	NM_182978.4
GNAL	ENST00000585590.1	n.11G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18463 AN: 151896 Hom.: 1277 Cov.: 33

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.0214

Gnomad SAS AF: 0.0814

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.115 AC: 9137 AN: 79358 Hom.: 617 AF XY: 0.116 AC XY: 5272 AN XY: 45594

Gnomad AFR exome AF: 0.0925

Gnomad AMR exome AF: 0.0706

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.00602

Gnomad SAS exome AF: 0.0913

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.146 AC: 192714 AN: 1320924 Hom.: 14996 Cov.: 32 AF XY: 0.145 AC XY: 94237 AN XY: 651018

Gnomad4 AFR exome AF: 0.0831

Gnomad4 AMR exome AF: 0.0841

Gnomad4 ASJ exome AF: 0.162

Gnomad4 EAS exome AF: 0.0319

Gnomad4 SAS exome AF: 0.0909

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.121 AC: 18459 AN: 152004 Hom.: 1276 Cov.: 33 AF XY: 0.119 AC XY: 8812 AN XY: 74324

Gnomad4 AFR AF: 0.0836

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.0215

Gnomad4 SAS AF: 0.0808

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.140

Alfa AF: 0.132 Hom.: 174

Bravo AF: 0.121

ExAC AF: 0.0469 AC: 2893

Asia WGS AF: 0.0440 AC: 152 AN: 3450

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.26
Dann	Benign	0.79
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.20
Sift	Benign	0.70	T
Sift4G	Benign	0.13	T
Vest4		0.0090
MPC		1.3
ClinPred		0.0018	T
GERP RS		-3.4
gMVP		0.17

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7236433; hg19: chr18-11689699; COSMIC: COSV61849575;