5-37812823-A-T

Variant names:

• chr5-37812823-A-T
• rs200003002
• NM_000514.4:c.*2828T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000514.4(GDNF):​c.*2828T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: GDNF NM_000514.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.421
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

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.*2828T>A		3_prime_UTR	Exon 3 of 3	NP_000505.1	P39905-1
	GDNF	NM_001190468.1		c.*2828T>A		3_prime_UTR	Exon 3 of 3	NP_001177397.1	P39905-3
	GDNF	NM_001190469.1		c.*2828T>A		3_prime_UTR	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.*2828T>A		3_prime_UTR	Exon 3 of 3	ENSP00000317145.2	P39905-1
	GDNF	ENST00000344622.8	TSL:1	c.*2828T>A		3_prime_UTR	Exon 3 of 3	ENSP00000339703.4	P39905-2
	GDNF	ENST00000620847.1	TSL:1	c.*2828T>A		3_prime_UTR	Exon 3 of 3	ENSP00000478722.1	P39905-5

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 20

Alfa AF: 0.0786 Hom.: 146

Bravo AF: 0.277

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hirschsprung disease, susceptibility to, 3 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.6
DANN	Benign	0.76
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200003002; hg19: chr5-37812925;