rs1110149

Positions:

• chr5-37823951-C-G

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.459

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:43592): (GDNF antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
GDNF	NM_000514.4	c.152-7816G>C		intron_variant		ENST00000326524.7	NP_000505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7	c.152-7816G>C		intron_variant		1	NM_000514.4	ENSP00000317145	P1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53485 AN: 152024 Hom.: 9900 Cov.: 33

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

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.327

Gnomad4 FIN exome AF: 0.461

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.368

GnomAD4 genome AF: 0.352 AC: 53493 AN: 152142 Hom.: 9904 Cov.: 33 AF XY: 0.348 AC XY: 25912 AN XY: 74376

Gnomad4 AFR AF: 0.241

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.377

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.386

Gnomad4 NFE AF: 0.420

Gnomad4 OTH AF: 0.377

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
DANN	Benign	0.67

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: rs1110149; hg19: chr5-37824053;