5-37813211-C-T

Variant names:

• chr5-37813211-C-T
• rs78865769
• NM_000514.4:c.*2440G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000514.4(GDNF):​c.*2440G>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 0.00444 in 152,124 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GDNF NM_000514.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.85
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-37813211-C-T is Benign according to our data. Variant chr5-37813211-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 353478.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0877 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.*2440G>A		3_prime_UTR	Exon 3 of 3	NP_000505.1	P39905-1
	GDNF	NM_001190468.1		c.*2440G>A		3_prime_UTR	Exon 3 of 3	NP_001177397.1	P39905-3
	GDNF	NM_001190469.1		c.*2440G>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.*2440G>A		3_prime_UTR	Exon 3 of 3	ENSP00000317145.2	P39905-1
	GDNF	ENST00000344622.8	TSL:1	c.*2440G>A		3_prime_UTR	Exon 3 of 3	ENSP00000339703.4	P39905-2
	GDNF	ENST00000620847.1	TSL:1	c.*2440G>A		3_prime_UTR	Exon 3 of 3	ENSP00000478722.1	P39905-5

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 672 AN: 152006 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0946

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00335

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 48 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 34

African (AFR) AF: 0.00 AC: 0 AN: 2

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: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 28

Other (OTH) AF: 0.00 AC: 0 AN: 16

GnomAD4 genome AF: 0.00444 AC: 675 AN: 152124 Hom.: 28 Cov.: 32 AF XY: 0.00499 AC XY: 371 AN XY: 74346

African (AFR) AF: 0.000747 AC: 31 AN: 41500

American (AMR) AF: 0.00608 AC: 93 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.0946 AC: 490 AN: 5178

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68006

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.00601

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hirschsprung disease, susceptibility to, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.23
DANN	Benign	0.70
PhyloP100		-2.9
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: rs78865769; hg19: chr5-37813313;