chr5-37813438-C-T

Variant names:

• chr5-37813438-C-T
• rs2973051
• NM_000514.4:c.*2213G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000514.4(GDNF):​c.*2213G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 151,894 control chromosomes in the GnomAD database, including 36,202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36199 hom., cov: 30)
  • Exomes 𝑓: 0.80 (3 hom.)
• Consequence: GDNF NM_000514.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.569
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

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.*2213G>A		3_prime_UTR	Exon 3 of 3	NP_000505.1	P39905-1
	GDNF	NM_001190468.1		c.*2213G>A		3_prime_UTR	Exon 3 of 3	NP_001177397.1	P39905-3
	GDNF	NM_001190469.1		c.*2213G>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.*2213G>A		3_prime_UTR	Exon 3 of 3	ENSP00000317145.2	P39905-1
	GDNF	ENST00000344622.8	TSL:1	c.*2213G>A		3_prime_UTR	Exon 3 of 3	ENSP00000339703.4	P39905-2
	GDNF	ENST00000620847.1	TSL:1	c.*2213G>A		3_prime_UTR	Exon 3 of 3	ENSP00000478722.1	P39905-5

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104247 AN: 151766 Hom.: 36164 Cov.: 30

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.662

Gnomad OTH AF: 0.681

GnomAD4 exome AF: 0.800 AC: 8 AN: 10 Hom.: 3 Cov.: 0 AF XY: 1.00 AC XY: 4 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 4 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.667 AC: 4 AN: 6

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.687 AC: 104334 AN: 151884 Hom.: 36199 Cov.: 30 AF XY: 0.681 AC XY: 50585 AN XY: 74228

African (AFR) AF: 0.784 AC: 32487 AN: 41418

American (AMR) AF: 0.672 AC: 10274 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2380 AN: 3466

East Asian (EAS) AF: 0.537 AC: 2772 AN: 5166

South Asian (SAS) AF: 0.591 AC: 2834 AN: 4798

European-Finnish (FIN) AF: 0.615 AC: 6448 AN: 10484

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.662 AC: 44981 AN: 67954

Other (OTH) AF: 0.676 AC: 1428 AN: 2112

Alfa AF: 0.677 Hom.: 44064

Bravo AF: 0.697

Asia WGS AF: 0.562 AC: 1957 AN: 3478

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	-0.91
CADD	Benign	0.17
DANN	Benign	0.59
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2973051; hg19: chr5-37813540;