rs3096140

Positions:

• chr5-37832731-G-A

Variant summary

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

The NM_000514.4(GDNF):​c.151+1915C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 152,082 control chromosomes in the GnomAD database, including 35,999 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 0.69 (35999 hom., cov: 32)
• Consequence: GDNF NM_000514.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.416

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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDNF	NM_000514.4	c.151+1915C>T		intron_variant		ENST00000326524.7	NP_000505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7	c.151+1915C>T		intron_variant		1	NM_000514.4	ENSP00000317145	P1

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104468 AN: 151964 Hom.: 35972 Cov.: 32

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.783

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.672

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.687 AC: 104541 AN: 152082 Hom.: 35999 Cov.: 32 AF XY: 0.689 AC XY: 51221 AN XY: 74352

Gnomad4 AFR AF: 0.681

Gnomad4 AMR AF: 0.717

Gnomad4 ASJ AF: 0.669

Gnomad4 EAS AF: 0.650

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.702

Gnomad4 NFE AF: 0.680

Gnomad4 OTH AF: 0.667

Alfa AF: 0.684 Hom.: 47983

Bravo AF: 0.685

Asia WGS AF: 0.726 AC: 2527 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.21
DANN	Benign	0.34

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: rs3096140; hg19: chr5-37832833;