5-37813447-C-A

Variant names:

• chr5-37813447-C-A
• rs72745194
• NM_000514.4:c.*2204G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000514.4(GDNF):​c.*2204G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0332 in 151,928 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (151 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GDNF NM_000514.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0440
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-37813447-C-A is Benign according to our data. Variant chr5-37813447-C-A is described in ClinVar as Benign. ClinVar VariationId is 353479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0766 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.*2204G>T		3_prime_UTR	Exon 3 of 3	NP_000505.1	P39905-1
	GDNF	NM_001190468.1		c.*2204G>T		3_prime_UTR	Exon 3 of 3	NP_001177397.1	P39905-3
	GDNF	NM_001190469.1		c.*2204G>T		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.*2204G>T		3_prime_UTR	Exon 3 of 3	ENSP00000317145.2	P39905-1
	GDNF	ENST00000344622.8	TSL:1	c.*2204G>T		3_prime_UTR	Exon 3 of 3	ENSP00000339703.4	P39905-2
	GDNF	ENST00000620847.1	TSL:1	c.*2204G>T		3_prime_UTR	Exon 3 of 3	ENSP00000478722.1	P39905-5

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5054 AN: 151812 Hom.: 151 Cov.: 31

Gnomad AFR AF: 0.0791

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0297

Gnomad FIN AF: 0.00456

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0283

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12

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: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0332 AC: 5050 AN: 151928 Hom.: 151 Cov.: 31 AF XY: 0.0330 AC XY: 2449 AN XY: 74256

African (AFR) AF: 0.0788 AC: 3262 AN: 41378

American (AMR) AF: 0.0184 AC: 281 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0295 AC: 142 AN: 4806

European-Finnish (FIN) AF: 0.00456 AC: 48 AN: 10520

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1090 AN: 67988

Other (OTH) AF: 0.0281 AC: 59 AN: 2102

Alfa AF: 0.0244 Hom.: 30

Bravo AF: 0.0361

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

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	-0.78
CADD	Benign	1.7
DANN	Benign	0.77
PhyloP100		0.044
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: rs72745194; hg19: chr5-37813549;