chr5-37823951-C-G

Variant names:

• chr5-37823951-C-G
• rs1110149
• NM_000514.4:c.152-7816G>C

Variant summary

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

The ENST00000326524.7(GDNF):​c.152-7816G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 530,974 control chromosomes in the GnomAD database, including 38,807 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 (9904 hom., cov: 33)
  • Exomes 𝑓: 0.39 (28903 hom.)
• Consequence: GDNF ENST00000326524.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.459
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000326524.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDNF	NM_000514.4	MANE Select	c.152-7816G>C		intron	N/A	NP_000505.1
	GDNF	NM_001190468.1		c.203-7816G>C		intron	N/A	NP_001177397.1
	GDNF	NM_001190469.1		c.125-7816G>C		intron	N/A	NP_001177398.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDNF	ENST00000326524.7	TSL:1 MANE Select	c.152-7816G>C		intron	N/A	ENSP00000317145.2
	GDNF	ENST00000427982.5	TSL:1	c.203-7816G>C		intron	N/A	ENSP00000409007.1
	GDNF	ENST00000381826.8	TSL:1	c.125-7816G>C		intron	N/A	ENSP00000371248.4

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53485 AN: 152024 Hom.: 9900 Cov.: 33

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.426

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.380

GnomAD4 exome AF: 0.390 AC: 147825 AN: 378832 Hom.: 28903 AF XY: 0.390 AC XY: 69568 AN XY: 178482

African (AFR) AF: 0.214 AC: 1567 AN: 7326

American (AMR) AF: 0.279 AC: 138 AN: 494

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 830 AN: 2324

East Asian (EAS) AF: 0.312 AC: 517 AN: 1658

South Asian (SAS) AF: 0.327 AC: 2414 AN: 7386

European-Finnish (FIN) AF: 0.461 AC: 47 AN: 102

Middle Eastern (MID) AF: 0.451 AC: 329 AN: 730

European-Non Finnish (NFE) AF: 0.397 AC: 137421 AN: 346428

Other (OTH) AF: 0.368 AC: 4562 AN: 12384

GnomAD4 genome AF: 0.352 AC: 53493 AN: 152142 Hom.: 9904 Cov.: 33 AF XY: 0.348 AC XY: 25912 AN XY: 74376

African (AFR) AF: 0.241 AC: 9992 AN: 41502

American (AMR) AF: 0.322 AC: 4930 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1309 AN: 3468

East Asian (EAS) AF: 0.332 AC: 1719 AN: 5172

South Asian (SAS) AF: 0.342 AC: 1650 AN: 4820

European-Finnish (FIN) AF: 0.386 AC: 4081 AN: 10586

Middle Eastern (MID) AF: 0.428 AC: 124 AN: 290

European-Non Finnish (NFE) AF: 0.420 AC: 28563 AN: 67990

Other (OTH) AF: 0.377 AC: 797 AN: 2112

Alfa AF: 0.377 Hom.: 1390

Bravo AF: 0.340

Asia WGS AF: 0.304 AC: 1059 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.2
DANN	Benign	0.67
PhyloP100		0.46
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: rs1110149; hg19: chr5-37824053;