5-37813447-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.*2204G>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 0.0332 in 151,928 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (151 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GDNF NM_000514.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0440

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=-0.78).
• BP6: Variant 5-37813447-C-A is Benign according to our data. Variant chr5-37813447-C-A is described in ClinVar as [Benign]. Clinvar id is 353479.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDNF	NM_000514.4	c.*2204G>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.*2204G>T		3_prime_UTR_variant	3/3	1	NM_000514.4	P1
GDNF	ENST00000344622.8	c.*2204G>T		3_prime_UTR_variant	3/3	1
GDNF	ENST00000620847.1	c.*2204G>T		3_prime_UTR_variant	3/3	1
GDNF-AS1	ENST00000637595.1	n.195-144C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5054 AN: 151812 Hom.: 151 Cov.: 31

Gnomad AFR AF: 0.0791

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0297

Gnomad FIN AF: 0.00456

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0283

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0332 AC: 5050 AN: 151928 Hom.: 151 Cov.: 31 AF XY: 0.0330 AC XY: 2449 AN XY: 74256

Gnomad4 AFR AF: 0.0788

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0295

Gnomad4 FIN AF: 0.00456

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0281

Alfa AF: 0.0233 Hom.: 20

Bravo AF: 0.0361

Asia WGS AF: 0.0120 AC: 43 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	-0.78
Cadd	Benign	1.7
Dann	Benign	0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72745194; hg19: chr5-37813549;