rs12413355

chr10-116214085-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005264.8(GFRA1):c.419-2440T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 151,872 control chromosomes in the GnomAD database, including 44,703 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 0.77 (44703 hom., cov: 30)
• Consequence: GFRA1 NM_005264.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.161

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA1	NM_005264.8	c.419-2440T>C		intron_variant		ENST00000355422.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA1	ENST00000355422.11	c.419-2440T>C		intron_variant		5	NM_005264.8	A2

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116413 AN: 151756 Hom.: 44682 Cov.: 30

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.730

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.788

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

GnomAD4 genome AF: 0.767 AC: 116483 AN: 151872 Hom.: 44703 Cov.: 30 AF XY: 0.764 AC XY: 56714 AN XY: 74186

Gnomad4 AFR AF: 0.743

Gnomad4 AMR AF: 0.824

Gnomad4 ASJ AF: 0.811

Gnomad4 EAS AF: 0.840

Gnomad4 SAS AF: 0.719

Gnomad4 FIN AF: 0.730

Gnomad4 NFE AF: 0.769

Gnomad4 OTH AF: 0.790

Alfa AF: 0.771 Hom.: 12029

Bravo AF: 0.778

Asia WGS AF: 0.797 AC: 2772 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.8
Dann	Benign	0.60

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: rs12413355; hg19: chr10-117973597;