Genetic Variant NM_182978.4:c.-41T>C (chr18-11689523-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182978.4(GNAL):c.-41T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,033,504 control chromosomes in the GnomAD database, including 41,303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 12875 hom., cov: 33)

Exomes 𝑓: 0.24 ( 28428 hom. )

Consequence

GNAL
NM_182978.4 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.774

Publications

7 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

GNAL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 18-11689523-T-C is Benign according to our data. Variant chr18-11689523-T-C is described in ClinVar as Benign. ClinVar VariationId is 1246973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	NM_182978.4	MANE Select	c.-41T>C		5_prime_UTR	Exon 1 of 12	NP_892023.1	P38405-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	ENST00000334049.11	TSL:1 MANE Select	c.-41T>C		5_prime_UTR	Exon 1 of 12	ENSP00000334051.5	P38405-2
	GNAL	ENST00000585590.1	TSL:2	n.-167T>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.349

AC:

53023

AN:

151806

Hom.:

12838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.691

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.283

Gnomad EAS

AF:

0.0231

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.333

GnomAD2 exomes

AF:

0.258

AC:

AN:

318

AF XY:

0.308

show subpopulations

Gnomad NFE exome

AF:

0.263

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.238

AC:

209505

AN:

881590

Hom.:

28428

Cov.:

AF XY:

0.237

AC XY:

99977

AN XY:

422180

show subpopulations

African (AFR)

AF:

0.706

AC:

13198

AN:

18700

American (AMR)

AF:

0.195

AC:

1479

AN:

7604

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

3516

AN:

12564

East Asian (EAS)

AF:

0.0330

AC:

797

AN:

24120

South Asian (SAS)

AF:

0.184

AC:

3263

AN:

17702

European-Finnish (FIN)

AF:

0.171

AC:

3670

AN:

21512

Middle Eastern (MID)

AF:

0.326

AC:

825

AN:

2530

European-Non Finnish (NFE)

AF:

0.235

AC:

173611

AN:

740212

Other (OTH)

AF:

0.250

AC:

9146

AN:

36646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

7494

14988

22483

29977

37471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6642

13284

19926

26568

33210

<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:

0.350

AC:

53101

AN:

151914

Hom.:

12875

Cov.:

AF XY:

0.341

AC XY:

25321

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.691

AC:

28671

AN:

41490

American (AMR)

AF:

0.226

AC:

3452

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.283

AC:

982

AN:

3468

East Asian (EAS)

AF:

0.0232

AC:

119

AN:

5132

South Asian (SAS)

AF:

0.180

AC:

871

AN:

4828

European-Finnish (FIN)

AF:

0.166

AC:

1748

AN:

10528

Middle Eastern (MID)

AF:

0.332

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.239

AC:

16254

AN:

67880

Other (OTH)

AF:

0.330

AC:

697

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1480

2961

4441

5922

7402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.123

Hom.:

198

Bravo

AF:

0.367

Asia WGS

AF:

0.116

AC:

399

AN:

3418

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Dystonia 25 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.2

(source)

DANN

Benign

0.64

PhyloP100

-0.77

PromoterAI

0.12

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over