rs2973042

chr5-37827657-T-G

Variant summary

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

The NM_000514.4(GDNF):c.151+6989A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 151,984 control chromosomes in the GnomAD database, including 9,320 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 (9320 hom., cov: 32)
• Consequence: GDNF NM_000514.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0840

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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDNF	NM_000514.4	c.151+6989A>C		intron_variant		ENST00000326524.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDNF	ENST00000326524.7	c.151+6989A>C		intron_variant		1	NM_000514.4	P1

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52513 AN: 151866 Hom.: 9309 Cov.: 32

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.305

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

GnomAD4 genome AF: 0.346 AC: 52562 AN: 151984 Hom.: 9320 Cov.: 32 AF XY: 0.351 AC XY: 26094 AN XY: 74314

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.426

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.328

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.368

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.303

Alfa AF: 0.318 Hom.: 7903

Bravo AF: 0.349

Asia WGS AF: 0.428 AC: 1486 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	2.5
Dann	Benign	0.76

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: rs2973042; hg19: chr5-37827759;