NM_000514.4:c.151+6989A>C

Variant names:

• chr5-37827657-T-G
• rs2973042
• NM_000514.4:c.151+6989A>C

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+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
• Publications: 6 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=-0.93).
• 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 rank	MANE	Protein	UniProt
GDNF	NM_000514.4	c.151+6989A>C		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+6989A>C		intron_variant	Intron 2 of 2	1	NM_000514.4	ENSP00000317145.2

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

African (AFR) AF: 0.360 AC: 14910 AN: 41448

American (AMR) AF: 0.426 AC: 6507 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1154 AN: 3468

East Asian (EAS) AF: 0.328 AC: 1695 AN: 5168

South Asian (SAS) AF: 0.456 AC: 2201 AN: 4824

European-Finnish (FIN) AF: 0.368 AC: 3891 AN: 10562

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21169 AN: 67934

Other (OTH) AF: 0.303 AC: 637 AN: 2104

Alfa AF: 0.322 Hom.: 10546

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
PhyloP100		0.084
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: rs2973042; hg19: chr5-37827759;