rs41289504

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_182978.4(GNAL):c.1245C>T(p.Ala415Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,614,020 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 12 hom., cov: 32)

Exomes 𝑓: 0.013 ( 138 hom. )

Consequence

GNAL
NM_182978.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.657

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 18-11881003-C-T is Benign according to our data. Variant chr18-11881003-C-T is described in ClinVar as Benign. ClinVar VariationId is 416012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.657 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00805 (1226/152320) while in subpopulation NFE AF = 0.0132 (898/68028). AF 95% confidence interval is 0.0125. There are 12 homozygotes in GnomAd4. There are 562 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1226 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAL	NM_182978.4 link	c.1245C>T	p.Ala415Ala	synonymous_variant	Exon 12 of 12	ENST00000334049.11	NP_892023.1	P38405-2
GNAL	NM_001369387.1 link	c.1014C>T	p.Ala338Ala	synonymous_variant	Exon 12 of 12	ENST00000423027.8	NP_001356316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11 link	c.1245C>T	p.Ala415Ala	synonymous_variant	Exon 12 of 12	1	NM_182978.4	ENSP00000334051.5		P38405-2
GNAL	ENST00000423027.8 link	c.1014C>T	p.Ala338Ala	synonymous_variant	Exon 12 of 12	1	NM_001369387.1	ENSP00000408489.2		P38405-1

Frequencies

GnomAD3 genomes

AF:

0.00805

AC:

1225

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00232

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00509

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0132

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00898

AC:

2253

AN:

250938

AF XY:

0.00911

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00480

Gnomad ASJ exome

AF:

0.0140

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00610

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0132

AC:

19269

AN:

1461700

Hom.:

138

Cov.:

AF XY:

0.0129

AC XY:

9353

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00254

AC:

AN:

33476

American (AMR)

AF:

0.00467

AC:

209

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0126

AC:

329

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00399

AC:

344

AN:

86236

European-Finnish (FIN)

AF:

0.00631

AC:

337

AN:

53412

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0156

AC:

17327

AN:

1111900

Other (OTH)

AF:

0.00952

AC:

575

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

919

1837

2756

3674

4593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

668

1336

2004

2672

3340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00805

AC:

1226

AN:

152320

Hom.:

Cov.:

AF XY:

0.00754

AC XY:

562

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00231

AC:

AN:

41572

American (AMR)

AF:

0.00549

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00249

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00509

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0132

AC:

898

AN:

68028

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

183

244

305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0117

Hom.:

Bravo

AF:

0.00824

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0131

EpiControl

AF:

0.0155

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GNAL: BP4, BP7, BS1, BS2 -

Oct 29, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dystonic disorder

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.5

(source)

DANN

Benign

0.92

PhyloP100

-0.66

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over