rs884344

Variant names:

• chr5-37824138-A-C
• rs884344
• NM_000514.4:c.152-8003T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000514.4(GDNF):​c.152-8003T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 531,210 control chromosomes in the GnomAD database, including 21,662 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 0.32 (8527 hom., cov: 32)
  • Exomes 𝑓: 0.26 (13135 hom.)
• Consequence: GDNF NM_000514.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.277
• Publications: 11 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000514.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDNF	NM_000514.4	MANE Select	c.152-8003T>G		intron	N/A	NP_000505.1	P39905-1
	GDNF	NM_001190468.1		c.203-8003T>G		intron	N/A	NP_001177397.1	P39905-3
	GDNF	NM_001190469.1		c.125-8003T>G		intron	N/A	NP_001177398.1	P39905-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDNF	ENST00000326524.7	TSL:1 MANE Select	c.152-8003T>G		intron	N/A	ENSP00000317145.2	P39905-1
	GDNF	ENST00000427982.5	TSL:1	c.203-8003T>G		intron	N/A	ENSP00000409007.1	P39905-3
	GDNF	ENST00000381826.8	TSL:1	c.125-8003T>G		intron	N/A	ENSP00000371248.4	P39905-4

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48671 AN: 151862 Hom.: 8497 Cov.: 32

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.284

GnomAD4 exome AF: 0.259 AC: 98036 AN: 379228 Hom.: 13135 Cov.: 5 AF XY: 0.260 AC XY: 46598 AN XY: 179416

African (AFR) AF: 0.501 AC: 3615 AN: 7218

American (AMR) AF: 0.369 AC: 174 AN: 472

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 622 AN: 2276

East Asian (EAS) AF: 0.230 AC: 381 AN: 1654

South Asian (SAS) AF: 0.280 AC: 2071 AN: 7406

European-Finnish (FIN) AF: 0.226 AC: 28 AN: 124

Middle Eastern (MID) AF: 0.232 AC: 170 AN: 732

European-Non Finnish (NFE) AF: 0.253 AC: 87641 AN: 346930

Other (OTH) AF: 0.269 AC: 3334 AN: 12416

GnomAD4 genome AF: 0.321 AC: 48749 AN: 151982 Hom.: 8527 Cov.: 32 AF XY: 0.321 AC XY: 23851 AN XY: 74264

African (AFR) AF: 0.474 AC: 19625 AN: 41420

American (AMR) AF: 0.334 AC: 5100 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 995 AN: 3468

East Asian (EAS) AF: 0.222 AC: 1145 AN: 5164

South Asian (SAS) AF: 0.281 AC: 1354 AN: 4814

European-Finnish (FIN) AF: 0.268 AC: 2834 AN: 10558

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

European-Non Finnish (NFE) AF: 0.247 AC: 16792 AN: 67962

Other (OTH) AF: 0.282 AC: 594 AN: 2108

Alfa AF: 0.277 Hom.: 19746

Bravo AF: 0.333

Asia WGS AF: 0.274 AC: 953 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.92
PhyloP100		0.28
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: rs884344; hg19: chr5-37824240;