rs104893891

Positions:

• chr5-37815827-T-A
• chr5-37815827-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GDNF ENST00000326524.7 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 7.67

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDNF	NM_000514.4	c.460A>T	p.Thr154Ser	missense_variant	3/3	ENST00000326524.7	NP_000505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDNF	ENST00000326524.7	c.460A>T	p.Thr154Ser	missense_variant	3/3	1	NM_000514.4	ENSP00000317145	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hirschsprung disease, susceptibility to, 3 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	.;.;D;.;.;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Uncertain	-0.062	T
MutationAssessor	Benign	1.4	.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	.;N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.24	.;T;T;T;T;T
Sift4G	Benign	0.42	T;T;T;T;T;T
Polyphen		1.0, 0.40, 0.0050, 0.40	.;D;B;B;B;D
Vest4		0.42
MutPred		0.77		.;.;Gain of disorder (P = 0.0444);.;.;.;
MVP		0.89
MPC		0.55
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.45
gMVP		0.74

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: rs104893891; hg19: chr5-37815929;