5-37835296-C-T

Position:

• chr5-37835296-C-T

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0500

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 = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDNF	NM_000514.4	c.-26-474G>A		intron_variant		ENST00000326524.7	NP_000505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7	c.-26-474G>A		intron_variant		1	NM_000514.4	ENSP00000317145.2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23810 AN: 151814 Hom.: 2189 Cov.: 31

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

Gnomad4 AFR exome AF: 0.243

Gnomad4 AMR exome AF: 0.0847

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.0309

Gnomad4 SAS exome AF: 0.0656

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.157 AC: 23865 AN: 151932 Hom.: 2198 Cov.: 31 AF XY: 0.156 AC XY: 11557 AN XY: 74264

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.0939

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.0292

Gnomad4 SAS AF: 0.0732

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.142

Alfa AF: 0.122 Hom.: 716

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
DANN	Benign	0.70

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: rs3812047; hg19: chr5-37835398;