Genetic Variant GDNF:c.152-8003T>G (chr5-37824138-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000514.4(GDNF):c.152-8003T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 531,210 control chromosomes in the GnomAD database, including 21,662 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.32 ( 8527 hom., cov: 32)

Exomes 𝑓: 0.26 ( 13135 hom. )

Consequence

GDNF
NM_000514.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.277

Publications

11 publications found

Variant links:

Genes affected

GDNF (HGNC:4232): (glial cell derived neurotrophic factor) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The recombinant form of this protein, a highly conserved neurotrophic factor, was shown to promote the survival and differentiation of dopaminergic neurons in culture, and was able to prevent apoptosis of motor neurons induced by axotomy. This protein is a ligand for the product of the RET (rearranged during transfection) protooncogene. Mutations in this gene may be associated with Hirschsprung disease and Tourette syndrome. This gene encodes multiple protein isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

GDNF links:

GDNF-AS1 (HGNC:43592): (GDNF antisense RNA 1)

GDNF-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDNF	NM_000514.4 link	c.152-8003T>G		intron_variant	Intron 2 of 2	ENST00000326524.7	NP_000505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7 link	c.152-8003T>G		intron_variant	Intron 2 of 2	1	NM_000514.4	ENSP00000317145.2

Frequencies

GnomAD3 genomes

AF:

0.320

AC:

48671

AN:

151862

Hom.:

8497

Cov.:

show subpopulations

Gnomad AFR

AF:

0.473

Gnomad AMI

AF:

0.261

Gnomad AMR

AF:

0.333

Gnomad ASJ

AF:

0.287

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.282

Gnomad FIN

AF:

0.268

Gnomad MID

AF:

0.242

Gnomad NFE

AF:

0.247

Gnomad OTH

AF:

0.284

GnomAD4 exome

AF:

0.259

AC:

98036

AN:

379228

Hom.:

13135

Cov.:

AF XY:

0.260

AC XY:

46598

AN XY:

179416

show subpopulations

African (AFR)

AF:

0.501

AC:

3615

AN:

7218

American (AMR)

AF:

0.369

AC:

174

AN:

472

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

622

AN:

2276

East Asian (EAS)

AF:

0.230

AC:

381

AN:

1654

South Asian (SAS)

AF:

0.280

AC:

2071

AN:

7406

European-Finnish (FIN)

AF:

0.226

AC:

AN:

124

Middle Eastern (MID)

AF:

0.232

AC:

170

AN:

732

European-Non Finnish (NFE)

AF:

0.253

AC:

87641

AN:

346930

Other (OTH)

AF:

0.269

AC:

3334

AN:

12416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

3532

7064

10597

14129

17661

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4108

8216

12324

16432

20540

<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:

0.321

AC:

48749

AN:

151982

Hom.:

8527

Cov.:

AF XY:

0.321

AC XY:

23851

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.474

AC:

19625

AN:

41420

American (AMR)

AF:

0.334

AC:

5100

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

995

AN:

3468

East Asian (EAS)

AF:

0.222

AC:

1145

AN:

5164

South Asian (SAS)

AF:

0.281

AC:

1354

AN:

4814

European-Finnish (FIN)

AF:

0.268

AC:

2834

AN:

10558

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.247

AC:

16792

AN:

67962

Other (OTH)

AF:

0.282

AC:

594

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1670

3340

5011

6681

8351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<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:

0.277

Hom.:

19746

Bravo

AF:

0.333

Asia WGS

AF:

0.274

AC:

953

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

0.28

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over