rs2694791

Positions:

• chr10-116105582-T-C

Variant summary

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

The NM_005264.8(GFRA1):​c.771-8818A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 152,182 control chromosomes in the GnomAD database, including 2,530 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 0.18 (2530 hom., cov: 33)
• Consequence: GFRA1 NM_005264.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.711

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 = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA1	NM_005264.8	c.771-8818A>G		intron_variant		ENST00000355422.11	NP_005255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422.11	c.771-8818A>G		intron_variant		5	NM_005264.8	ENSP00000347591	A2

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27525 AN: 152066 Hom.: 2528 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.198

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

GnomAD4 genome AF: 0.181 AC: 27559 AN: 152182 Hom.: 2530 Cov.: 33 AF XY: 0.180 AC XY: 13384 AN XY: 74410

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.200

Alfa AF: 0.189 Hom.: 336

Bravo AF: 0.178

Asia WGS AF: 0.225 AC: 781 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	0.21
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2694791; hg19: chr10-117865093;