rs884344

Positions:

• chr5-37824138-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.277

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
GDNF	NM_000514.4	c.152-8003T>G		intron_variant		ENST00000326524.7	NP_000505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7	c.152-8003T>G		intron_variant		1	NM_000514.4	ENSP00000317145.2

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48671 AN: 151862 Hom.: 8497 Cov.: 32

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.: 5 AF XY: 0.260 AC XY: 46598 AN XY: 179416

Gnomad4 AFR exome AF: 0.501

Gnomad4 AMR exome AF: 0.369

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.230

Gnomad4 SAS exome AF: 0.280

Gnomad4 FIN exome AF: 0.226

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.269

GnomAD4 genome AF: 0.321 AC: 48749 AN: 151982 Hom.: 8527 Cov.: 32 AF XY: 0.321 AC XY: 23851 AN XY: 74264

Gnomad4 AFR AF: 0.474

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.287

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.281

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.282

Alfa AF: 0.261 Hom.: 10953

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	13
DANN	Benign	0.92

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

LitVar

Other links and lift over

dbSNP: rs884344; hg19: chr5-37824240;