rs36119840

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000514.4(GDNF):c.277C>T(p.Arg93Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00357 in 1,613,822 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 15 hom. )

Consequence

GDNF
NM_000514.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 4.16

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073699653).

BP6

Variant 5-37816010-G-A is Benign according to our data. Variant chr5-37816010-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 8758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37816010-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 402 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDNF	NM_000514.4 link	c.277C>T	p.Arg93Trp	missense_variant	Exon 3 of 3	ENST00000326524.7	NP_000505.1	P39905-1A0A0S2Z3V2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7 link	c.277C>T	p.Arg93Trp	missense_variant	Exon 3 of 3	1	NM_000514.4	ENSP00000317145.2		P39905-1

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

402

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00438

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00225

AC:

566

AN:

251340

Hom.:

AF XY:

0.00230

AC XY:

313

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00382

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00367

AC:

5365

AN:

1461508

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

2583

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00242

Gnomad4 ASJ exome

AF:

0.00249

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00442

Gnomad4 OTH exome

AF:

0.00368

GnomAD4 genome

AF:

0.00264

AC:

402

AN:

152314

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

164

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00438

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00358

Hom.:

Bravo

AF:

0.00289

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00221

AC:

268

EpiCase

AF:

0.00534

EpiControl

AF:

0.00474

ClinVar

Significance: Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GDNF: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hirschsprung disease, susceptibility to, 3

Benign:2Other:1

Apr 01, 2003

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Sep 10, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg110Trp in exon 3 of GDNF: This variant has been reported in individuals with various phenotypes including pulmonary presentations (see below). However, it i s not expected to cause disease on its own because it has been identified in 0.3 % (28/8600) of European American chromosomes by the NHLBI Exome Sequencing Proje ct (http://evs.gs.washington.edu/EVS/; dbSNP rs36119840). Phenotypes of individu als reported to carry this variant include isolated congenital central hypoventi lation syndrome, sporadic pheochromocytoma, Hirschsprung disease, and congenital anomalies of the kidney or urinary tract (reported as Arg93Trp; Angrist 1996, S olomon 1996, Woodward 1997, Amiel 1998, Amiel 2003, Chatterjee 2012). In vitro f unctional studies provide some evidence that the Arg110Trp variant may not impac t protein function (reported as Arg93Trp; Eketjall 2002). In summary, this varia nt is not expected to be disease-causing when seen in isolation, though a modify ing role cannot be fully excluded. -

GDNF-related disorder

Benign:1

Apr 22, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;.;D;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

D;D;D;D;D;.

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.0074

T;T;T;T;T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

1.9

.;.;L;.;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.2

.;N;N;D;N;N

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0020

.;D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

1.0, 1.0

.;D;D;D;D;D

Vest4

0.26

MVP

0.92

MPC

1.4

ClinPred

0.029

GERP RS

5.0

Varity_R

0.31

gMVP

0.64

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