Genetic Variant GNAL:p.Val214Met (chr18-11824933-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182978.4(GNAL):c.640G>A(p.Val214Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAL
NM_182978.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 3.96

Publications

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

GNAL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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
GNAL	NM_182978.4	MANE Select	c.640G>A	p.Val214Met	missense	Exon 5 of 12	NP_892023.1
GNAL	NM_001369387.1	MANE Plus Clinical	c.409G>A	p.Val137Met	missense	Exon 5 of 12	NP_001356316.1
GNAL	NM_001142339.3		c.409G>A	p.Val137Met	missense	Exon 6 of 13	NP_001135811.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNAL	ENST00000334049.11	TSL:1 MANE Select	c.640G>A	p.Val214Met	missense	Exon 5 of 12	ENSP00000334051.5
GNAL	ENST00000423027.8	TSL:1 MANE Plus Clinical	c.409G>A	p.Val137Met	missense	Exon 5 of 12	ENSP00000408489.2
GNAL	ENST00000535121.5	TSL:1	c.409G>A	p.Val137Met	missense	Exon 6 of 13	ENSP00000439023.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1431776

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713558

African (AFR)

AF:

0.00

AC:

AN:

32490

American (AMR)

AF:

0.00

AC:

AN:

43206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25874

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.00

AC:

AN:

83832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088452

Other (OTH)

AF:

0.00

AC:

AN:

59374

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dystonia 25

Pathogenic:1

Jan 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Uncertain:1

Feb 20, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that the variant results in little to modest effect on the protein (PMID: 30021154); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26725140, Giri2017[Thesis], 29948482, 24136457, 23775978, 24952478, 30021154, 23222958)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.70

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.54

PhyloP100

4.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.63

Sift

Benign

0.36

Sift4G

Benign

0.35

Polyphen

0.40

Vest4

0.47

MutPred

0.59

Gain of ubiquitination at K139 (P = 0.1064)

MVP

0.92

MPC

2.4

ClinPred

0.78

GERP RS

5.7

Varity_R

0.27

gMVP

0.70

Mutation Taster

=1/99

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over