rs121918536

Positions:

chr5-37815654-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_000514.4(GDNF):c.633C>G(p.Ile211Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

GDNF
NM_000514.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 2.68

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:):

GDNF-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2915848).

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDNF	NM_000514.4 linkuse as main transcript	c.633C>G	p.Ile211Met	missense_variant	3/3	ENST00000326524.7	NP_000505.1	P39905-1A0A0S2Z3V2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7 linkuse as main transcript	c.633C>G	p.Ile211Met	missense_variant	3/3	1	NM_000514.4	ENSP00000317145.2		P39905-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000994

AC:

AN:

251428

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000113

AC:

165

AN:

1461060

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

726900

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000146

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000109

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 22, 2024

Variant summary: GDNF c.633C>G (p.Ile211Met) results in a conservative amino acid change located in the Transforming growth factor-beta, C-terminal domain (IPR001839) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251428 control chromosomes, predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GDNF causing Hirschsprung Disease, Susceptibility To, 3, allowing no conclusion about variant significance. c.633C>G has been reported in the literature in individuals affected with Hirschsprung Disease and Kidney and/or genitourinary disorder (example, Martucciello_2000, Rasouly_2019), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hirschsprung Disease, Susceptibility To, 3. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Eketjall_2002). The following publications have been ascertained in the context of this evaluation (PMID: 11823451, 10917288, 26489027, 30476936). ClinVar contains an entry for this variant (Variation ID: 8761). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hirschsprung disease, susceptibility to, 3

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.0014

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

.;.;D;.;.;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D;D;D;D;.

M_CAP

Benign

0.045

MetaRNN

Benign

0.29

T;T;T;T;T;T

MetaSVM

Uncertain

0.055

MutationAssessor

Benign

1.1

.;.;L;.;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.7

.;N;N;N;N;N

REVEL

Uncertain

0.56

Sift

Uncertain

0.0020

.;D;D;T;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

0.49, 0.64, 0.75, 0.58

.;P;P;P;P;P

Vest4

0.34

MVP

0.92

MPC

0.88

ClinPred

0.19

GERP RS

5.9

Varity_R

0.86

gMVP

0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over