Genetic Variant NM_000514.4:c.152-7816G>C (chr5-37823951-C-G) – 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.152-7816G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 530,974 control chromosomes in the GnomAD database, including 38,807 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 0.35 ( 9904 hom., cov: 33)

Exomes 𝑓: 0.39 ( 28903 hom. )

Consequence

GDNF
NM_000514.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.459

Publications

6 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=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDNF	NM_000514.4 link	c.152-7816G>C		intron_variant	Intron 2 of 2	ENST00000326524.7	NP_000505.1	P39905-1A0A0S2Z3V2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7 link	c.152-7816G>C		intron_variant	Intron 2 of 2	1	NM_000514.4	ENSP00000317145.2		P39905-1

Frequencies

GnomAD3 genomes

AF:

0.352

AC:

53485

AN:

152024

Hom.:

9900

Cov.:

show subpopulations

Gnomad AFR

AF:

0.241

Gnomad AMI

AF:

0.360

Gnomad AMR

AF:

0.323

Gnomad ASJ

AF:

0.377

Gnomad EAS

AF:

0.333

Gnomad SAS

AF:

0.342

Gnomad FIN

AF:

0.386

Gnomad MID

AF:

0.426

Gnomad NFE

AF:

0.420

Gnomad OTH

AF:

0.380

GnomAD4 exome

AF:

0.390

AC:

147825

AN:

378832

Hom.:

28903

AF XY:

0.390

AC XY:

69568

AN XY:

178482

show subpopulations

African (AFR)

AF:

0.214

AC:

1567

AN:

7326

American (AMR)

AF:

0.279

AC:

138

AN:

494

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

830

AN:

2324

East Asian (EAS)

AF:

0.312

AC:

517

AN:

1658

South Asian (SAS)

AF:

0.327

AC:

2414

AN:

7386

European-Finnish (FIN)

AF:

0.461

AC:

AN:

102

Middle Eastern (MID)

AF:

0.451

AC:

329

AN:

730

European-Non Finnish (NFE)

AF:

0.397

AC:

137421

AN:

346428

Other (OTH)

AF:

0.368

AC:

4562

AN:

12384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

4194

8388

12582

16776

20970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5838

11676

17514

23352

29190

<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:

0.352

AC:

53493

AN:

152142

Hom.:

9904

Cov.:

AF XY:

0.348

AC XY:

25912

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.241

AC:

9992

AN:

41502

American (AMR)

AF:

0.322

AC:

4930

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.377

AC:

1309

AN:

3468

East Asian (EAS)

AF:

0.332

AC:

1719

AN:

5172

South Asian (SAS)

AF:

0.342

AC:

1650

AN:

4820

European-Finnish (FIN)

AF:

0.386

AC:

4081

AN:

10586

Middle Eastern (MID)

AF:

0.428

AC:

124

AN:

290

European-Non Finnish (NFE)

AF:

0.420

AC:

28563

AN:

67990

Other (OTH)

AF:

0.377

AC:

797

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1805

3610

5414

7219

9024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

532

1064

1596

2128

2660

<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:

0.377

Hom.:

1390

Bravo

AF:

0.340

Asia WGS

AF:

0.304

AC:

1059

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.2

(source)

DANN

Benign

0.67

PhyloP100

0.46

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