dbSNP rs398122924: GNAL:p.Ser370* (chr18-11872345-C-A) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_182978.4(GNAL):c.1109C>A(p.Ser370*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAL
NM_182978.4 stop_gained

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.50

Publications

4 publications found

Variant links:

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, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

GNAL links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_182978.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-11872345-C-A is Pathogenic according to our data. Variant chr18-11872345-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39968.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182978.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNAL	NM_182978.4	MANE Select	c.1109C>A	p.Ser370*	stop_gained	Exon 10 of 12	NP_892023.1	P38405-2
GNAL	NM_001369387.1	MANE Plus Clinical	c.878C>A	p.Ser293*	stop_gained	Exon 10 of 12	NP_001356316.1	A8K1Y9
GNAL	NM_001142339.3		c.878C>A	p.Ser293*	stop_gained	Exon 11 of 13	NP_001135811.1	A8K1Y9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNAL	ENST00000334049.11	TSL:1 MANE Select	c.1109C>A	p.Ser370*	stop_gained	Exon 10 of 12	ENSP00000334051.5	P38405-2
GNAL	ENST00000423027.8	TSL:1 MANE Plus Clinical	c.878C>A	p.Ser293*	stop_gained	Exon 10 of 12	ENSP00000408489.2	P38405-1
GNAL	ENST00000535121.5	TSL:1	c.878C>A	p.Ser293*	stop_gained	Exon 11 of 13	ENSP00000439023.1	P38405-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

706272

African (AFR)

AF:

0.00

AC:

AN:

30646

American (AMR)

AF:

0.00

AC:

AN:

33506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24876

East Asian (EAS)

AF:

0.00

AC:

AN:

38390

South Asian (SAS)

AF:

0.00

AC:

AN:

79988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093254

Other (OTH)

AF:

0.00

AC:

AN:

58672

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dystonia 25 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.95

PhyloP100

7.5

PromoterAI

-0.026

Neutral

(source)

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over