rs36119840

chr5-37816010-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 4.16

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 -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 GnomAd at 402 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDNF	NM_000514.4	c.277C>T	p.Arg93Trp	missense_variant	3/3	ENST00000326524.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDNF	ENST00000326524.7	c.277C>T	p.Arg93Trp	missense_variant	3/3	1	NM_000514.4	P1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152196 Hom.: 2 Cov.: 33

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.: 1 AF XY: 0.00230 AC XY: 313 AN XY: 135848

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.: 15 Cov.: 33 AF XY: 0.00355 AC XY: 2583 AN XY: 727000

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.: 2 Cov.: 33 AF XY: 0.00220 AC XY: 164 AN XY: 74486

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.: 3

Bravo AF: 0.00289

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00221 AC: 268

EpiCase AF: 0.00534

EpiControl AF: 0.00474

ClinVar

Significance: Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hirschsprung disease, susceptibility to, 3 Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 03, 2022	- -
risk factor, no assertion criteria provided	literature only	OMIM	Apr 01, 2003	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	GDNF: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 10, 2014

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2021

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	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.0074	T;T;T;T;T;T
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.37	T
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	T
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

Other links and lift over

dbSNP: rs36119840; hg19: chr5-37816112; COSMIC: COSV58481658; COSMIC: COSV58481658;