18-11689828-G-A

Position:

• chr18-11689828-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182978.4(GNAL):​c.265G>A​(p.Ala89Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,384,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GNAL NM_182978.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19024685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAL	NM_182978.4	c.265G>A	p.Ala89Thr	missense_variant	1/12	ENST00000334049.11	NP_892023.1
GNAL	XM_006722324.4	c.265G>A	p.Ala89Thr	missense_variant	1/6		XP_006722387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11	c.265G>A	p.Ala89Thr	missense_variant	1/12	1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000585590.1	n.139G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1384822 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 685042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.29e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.0061
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	-0.17	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.28
Sift	Benign	0.12	T
Sift4G	Benign	0.20	T
Vest4		0.051
MutPred		0.27		Gain of phosphorylation at A89 (P = 7e-04);
MVP		0.72
MPC		1.3
ClinPred		0.93	D
GERP RS		2.2
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: rs1555639311; hg19: chr18-11689827;