rs11111

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.626

Publications

14 publications found

Variant links:

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 links:

GDNF-AS1 (HGNC:43592): (GDNF antisense RNA 1)

GDNF-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
GDNF	NM_000514.4 link	c.*1651A>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000326524.7	NP_000505.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
GDNF	ENST00000326524.7 link	c.*1651A>G	3_prime_UTR_variant	Exon 3 of 3	1	NM_000514.4	ENSP00000317145.2
GDNF	ENST00000344622.8 link	c.*1651A>G	3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000339703.4
GDNF	ENST00000620847.1 link	c.*1651A>G	3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000478722.1
GDNF-AS1	ENST00000637595.1 link	n.310-198T>C	intron_variant	Intron 2 of 11	5

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33604

AN:

151892

Hom.:

4136

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.188

AC XY:

AN XY:

416

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.143

AC:

AN:

South Asian (SAS)

AF:

0.250

AC:

AN:

European-Finnish (FIN)

AF:

0.179

AC:

AN:

442

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.199

AC:

AN:

166

Other (OTH)

AF:

0.167

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.221

AC:

33638

AN:

152010

Hom.:

4142

Cov.:

AF XY:

0.223

AC XY:

16579

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.321

AC:

13306

AN:

41422

American (AMR)

AF:

0.283

AC:

4337

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.205

AC:

710

AN:

3464

East Asian (EAS)

AF:

0.218

AC:

1121

AN:

5146

South Asian (SAS)

AF:

0.238

AC:

1148

AN:

4824

European-Finnish (FIN)

AF:

0.165

AC:

1745

AN:

10576

Middle Eastern (MID)

AF:

0.186

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.157

AC:

10653

AN:

67968

Other (OTH)

AF:

0.201

AC:

423

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1312

2625

3937

5250

6562

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.186

Hom.:

9172

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

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hirschsprung disease, susceptibility to, 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

1.2

(source)

DANN

Benign

0.47

PhyloP100

-0.63

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over