rs3096140

Variant names:

• chr5-37832731-G-A
• rs3096140
• NM_000514.4:c.151+1915C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
GDNF	NM_000514.4	c.151+1915C>T		intron_variant	Intron 2 of 2	ENST00000326524.7	NP_000505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7	c.151+1915C>T		intron_variant	Intron 2 of 2	1	NM_000514.4	ENSP00000317145.2

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

African (AFR) AF: 0.681 AC: 28245 AN: 41480

American (AMR) AF: 0.717 AC: 10962 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2323 AN: 3472

East Asian (EAS) AF: 0.650 AC: 3358 AN: 5164

South Asian (SAS) AF: 0.783 AC: 3780 AN: 4826

European-Finnish (FIN) AF: 0.702 AC: 7421 AN: 10566

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.680 AC: 46196 AN: 67972

Other (OTH) AF: 0.667 AC: 1411 AN: 2114

Alfa AF: 0.684 Hom.: 60775

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
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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: rs3096140; hg19: chr5-37832833;