rs3812047

Variant names:

• chr5-37835296-C-G
• rs3812047
• NM_000514.4:c.-26-474G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-37835296-C-G
• chr5-37835296-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000514.4(GDNF):​c.-26-474G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 300,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: GDNF NM_000514.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0500
• Publications: 19 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDNF	NM_000514.4	c.-26-474G>C		intron_variant	Intron 1 of 2	ENST00000326524.7	NP_000505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7	c.-26-474G>C		intron_variant	Intron 1 of 2	1	NM_000514.4	ENSP00000317145.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000133 AC: 4 AN: 300870 Hom.: 0 AF XY: 0.00000646 AC XY: 1 AN XY: 154720

African (AFR) AF: 0.00 AC: 0 AN: 8560

American (AMR) AF: 0.00 AC: 0 AN: 9788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8378

East Asian (EAS) AF: 0.00 AC: 0 AN: 16178

South Asian (SAS) AF: 0.00 AC: 0 AN: 24536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1314

European-Non Finnish (NFE) AF: 0.0000199 AC: 4 AN: 201220

Other (OTH) AF: 0.00 AC: 0 AN: 16980

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 832

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.0
DANN	Benign	0.45
PhyloP100		-0.050
PromoterAI		0.039	Neutral

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

Other links and lift over

dbSNP: rs3812047; hg19: chr5-37835398;