rs2420257

Positions:

• chr10-116248830-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_005264.8(GFRA1):​c.418+20673C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,038 control chromosomes in the GnomAD database, including 5,763 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (5763 hom., cov: 32)
• Consequence: GFRA1 NM_005264.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

Genes affected

GFRA1 (HGNC:4243): (GDNF family receptor alpha 1) This gene encodes a member of the glial cell line-derived neurotrophic factor receptor (GDNFR) family of proteins. The encoded preproprotein is proteolytically processed to generate the mature receptor. Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. This receptor is a glycosylphosphatidylinositol (GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for Hirschsprung disease. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA1	NM_005264.8	c.418+20673C>T		intron_variant		ENST00000355422.11	NP_005255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422.11	c.418+20673C>T		intron_variant		5	NM_005264.8	ENSP00000347591	A2

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41398 AN: 151920 Hom.: 5758 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.248

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.273 AC: 41431 AN: 152038 Hom.: 5763 Cov.: 32 AF XY: 0.278 AC XY: 20696 AN XY: 74322

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.347

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.248

Alfa AF: 0.254 Hom.: 735

Bravo AF: 0.277

Asia WGS AF: 0.331 AC: 1148 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.86

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: rs2420257; hg19: chr10-118008342;