5-37813489-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000514.4(GDNF):c.*2162G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 150,840 control chromosomes in the GnomAD database, including 7,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (7226 hom., cov: 28)
  • Exomes 𝑓: 0.53 (6 hom.)
• Consequence: GDNF NM_000514.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.317

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-37813489-C-A is Benign according to our data. Variant chr5-37813489-C-A is described in ClinVar as [Benign]. Clinvar id is 353480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDNF	NM_000514.4	c.*2162G>T		3_prime_UTR_variant	3/3	ENST00000326524.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDNF	ENST00000326524.7	c.*2162G>T		3_prime_UTR_variant	3/3	1	NM_000514.4	P1
GDNF	ENST00000344622.8	c.*2162G>T		3_prime_UTR_variant	3/3	1
GDNF	ENST00000620847.1	c.*2162G>T		3_prime_UTR_variant	3/3	1
GDNF-AS1	ENST00000637595.1	n.195-102C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.298 AC: 44887 AN: 150706 Hom.: 7227 Cov.: 28

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.337

GnomAD4 exome AF: 0.528 AC: 19 AN: 36 Hom.: 6 Cov.: 0 AF XY: 0.462 AC XY: 12 AN XY: 26

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.298 AC: 44891 AN: 150804 Hom.: 7226 Cov.: 28 AF XY: 0.292 AC XY: 21442 AN XY: 73528

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.288

Gnomad4 ASJ AF: 0.285

Gnomad4 EAS AF: 0.285

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.371

Gnomad4 OTH AF: 0.334

Alfa AF: 0.350 Hom.: 19880

Bravo AF: 0.291

Asia WGS AF: 0.232 AC: 808 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hirschsprung disease, susceptibility to, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.38
Dann	Benign	0.52

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17379771; hg19: chr5-37813591;