rs756312071

Variant names:

• chr5-37815860-T-C
• rs756312071
• NM_000514.4:c.427A>G
• GDNF p.Arg143Gly

Your query was ambiguous. Multiple possible variants found:

• chr5-37815860-T-C
• chr5-37815860-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000514.4(GDNF):​c.427A>G​(p.Arg143Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R143R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GDNF NM_000514.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.435
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000514.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDNF	NM_000514.4	MANE Select	c.427A>G	p.Arg143Gly	missense	Exon 3 of 3	NP_000505.1	P39905-1
	GDNF	NM_001190468.1		c.478A>G	p.Arg160Gly	missense	Exon 3 of 3	NP_001177397.1	P39905-3
	GDNF	NM_001190469.1		c.400A>G	p.Arg134Gly	missense	Exon 3 of 3	NP_001177398.1	P39905-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDNF	ENST00000326524.7	TSL:1 MANE Select	c.427A>G	p.Arg143Gly	missense	Exon 3 of 3	ENSP00000317145.2	P39905-1
	GDNF	ENST00000427982.5	TSL:1	c.478A>G	p.Arg160Gly	missense	Exon 3 of 3	ENSP00000409007.1	P39905-3
	GDNF	ENST00000381826.8	TSL:1	c.400A>G	p.Arg134Gly	missense	Exon 3 of 3	ENSP00000371248.4	P39905-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.43
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.92
gMVP		0.88
Mutation Taster		=38/62	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs756312071;

hg19: chr5-37815962;