Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000326524.7(GDNF):c.460A>T(p.Thr154Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T154K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GDNF
ENST00000326524.7 missense

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 7.67

Publications

4 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GDNF	NM_000514.4	MANE Select	c.460A>T	p.Thr154Ser	missense	Exon 3 of 3	NP_000505.1
GDNF	NM_001190468.1		c.511A>T	p.Thr171Ser	missense	Exon 3 of 3	NP_001177397.1
GDNF	NM_001190469.1		c.433A>T	p.Thr145Ser	missense	Exon 3 of 3	NP_001177398.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GDNF	ENST00000326524.7	TSL:1 MANE Select	c.460A>T	p.Thr154Ser	missense	Exon 3 of 3	ENSP00000317145.2
GDNF	ENST00000427982.5	TSL:1	c.511A>T	p.Thr171Ser	missense	Exon 3 of 3	ENSP00000409007.1
GDNF	ENST00000381826.8	TSL:1	c.433A>T	p.Thr145Ser	missense	Exon 3 of 3	ENSP00000371248.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:risk factor

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hirschsprung disease, susceptibility to, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.088

MetaRNN

Uncertain

0.61

MetaSVM

Uncertain

-0.062

MutationAssessor

Benign

1.4

PhyloP100

7.7

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.62

Sift

Benign

0.24

Sift4G

Benign

0.42

Polyphen

1.0

Vest4

0.42

MutPred

0.77

Gain of disorder (P = 0.0444)

MVP

0.89

MPC

0.55

ClinPred

0.89

GERP RS

4.6

Varity_R

0.45

gMVP

0.74

Mutation Taster

=5/95

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr5-37815827-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over