Genetic Variant NM_000514.4:c.-26-474G>A (chr5-37835296-C-T) – 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.-26-474G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 452,296 control chromosomes in the GnomAD database, including 4,876 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 0.16 ( 2198 hom., cov: 31)

Exomes 𝑓: 0.12 ( 2678 hom. )

Consequence

GDNF
NM_000514.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0500

Publications

19 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 = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDNF	NM_000514.4 link	c.-26-474G>A		intron_variant	Intron 1 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.-26-474G>A		intron_variant	Intron 1 of 2	1	NM_000514.4	ENSP00000317145.2		P39905-1

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23810

AN:

151814

Hom.:

2189

Cov.:

show subpopulations

Gnomad AFR

AF:

0.245

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.0939

Gnomad ASJ

AF:

0.166

Gnomad EAS

AF:

0.0289

Gnomad SAS

AF:

0.0733

Gnomad FIN

AF:

0.134

Gnomad MID

AF:

0.134

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.137

GnomAD4 exome

AF:

0.125

AC:

37412

AN:

300364

Hom.:

2678

AF XY:

0.122

AC XY:

18770

AN XY:

154468

show subpopulations

African (AFR)

AF:

0.243

AC:

2078

AN:

8548

American (AMR)

AF:

0.0847

AC:

828

AN:

9772

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

1405

AN:

8368

East Asian (EAS)

AF:

0.0309

AC:

499

AN:

16170

South Asian (SAS)

AF:

0.0656

AC:

1607

AN:

24506

European-Finnish (FIN)

AF:

0.131

AC:

1819

AN:

13884

Middle Eastern (MID)

AF:

0.134

AC:

175

AN:

1310

European-Non Finnish (NFE)

AF:

0.133

AC:

26762

AN:

200848

Other (OTH)

AF:

0.132

AC:

2239

AN:

16958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1559

3118

4676

6235

7794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

398

796

1194

1592

1990

<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:

0.157

AC:

23865

AN:

151932

Hom.:

2198

Cov.:

AF XY:

0.156

AC XY:

11557

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.246

AC:

10176

AN:

41410

American (AMR)

AF:

0.0939

AC:

1434

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.166

AC:

577

AN:

3468

East Asian (EAS)

AF:

0.0292

AC:

150

AN:

5142

South Asian (SAS)

AF:

0.0732

AC:

352

AN:

4810

European-Finnish (FIN)

AF:

0.134

AC:

1411

AN:

10554

Middle Eastern (MID)

AF:

0.123

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.138

AC:

9364

AN:

67968

Other (OTH)

AF:

0.142

AC:

298

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

996

1991

2987

3982

4978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.125

Hom.:

832

Bravo

AF:

0.160

Asia WGS

AF:

0.0780

AC:

270

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

7.0

(source)

DANN

Benign

0.70

PhyloP100

-0.050

PromoterAI

-0.028

Neutral

(source)

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