rs11111

Positions:

• chr5-37814000-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000514.4(GDNF):​c.*1651A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,664 control chromosomes in the GnomAD database, including 4,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4142 hom., cov: 30)
  • Exomes 𝑓: 0.19 (10 hom.)
• Consequence: GDNF NM_000514.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.626

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-37814000-T-C is Benign according to our data. Variant chr5-37814000-T-C is described in ClinVar as [Benign]. Clinvar id is 353491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDNF	NM_000514.4	c.*1651A>G		3_prime_UTR_variant	3/3	ENST00000326524.7	NP_000505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7	c.*1651A>G		3_prime_UTR_variant	3/3	1	NM_000514.4	ENSP00000317145	P1
GDNF	ENST00000344622.8	c.*1651A>G		3_prime_UTR_variant	3/3	1		ENSP00000339703
GDNF	ENST00000620847.1	c.*1651A>G		3_prime_UTR_variant	3/3	1		ENSP00000478722
GDNF-AS1	ENST00000637595.1	n.310-198T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33604 AN: 151892 Hom.: 4136 Cov.: 30

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.179

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.202

GnomAD4 exome AF: 0.188 AC: 123 AN: 654 Hom.: 10 Cov.: 0 AF XY: 0.188 AC XY: 78 AN XY: 416

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 1.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.250

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.199

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.221 AC: 33638 AN: 152010 Hom.: 4142 Cov.: 30 AF XY: 0.223 AC XY: 16579 AN XY: 74298

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.283

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.201

Alfa AF: 0.177 Hom.: 3528

Bravo AF: 0.235

Asia WGS AF: 0.240 AC: 837 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.47

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11111; hg19: chr5-37814102; COSMIC: COSV58478868; COSMIC: COSV58478868;