8-21804933-C-A

Variant names:

• chr8-21804933-C-A
• rs17581368
• ENST00000517328.5:c.-36+84G>T

Variant summary

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

The ENST00000517328.5(GFRA2):​c.-36+84G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 151,876 control chromosomes in the GnomAD database, including 11,675 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 0.39 (11669 hom., cov: 31)
  • Exomes 𝑓: 0.40 (6 hom.)
• Consequence: GFRA2 ENST00000517328.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56

Genes affected

GFRA2 (HGNC:4244): (GDNF family receptor alpha 2) 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. The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This encoded protein acts preferentially as a receptor for NTN compared to its other family member, GDNF family receptor alpha 1. This gene is a candidate gene for RET-associated diseases. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFRA2	XM_047421687.1	c.-36+7298G>T		intron_variant	Intron 1 of 9		XP_047277643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFRA2	ENST00000517328.5	c.-36+84G>T		intron_variant	Intron 2 of 10	5		ENSP00000429445.1

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58503 AN: 151678 Hom.: 11652 Cov.: 31

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.343

GnomAD4 exome AF: 0.400 AC: 32 AN: 80 Hom.: 6 AF XY: 0.464 AC XY: 26 AN XY: 56

Gnomad4 AFR exome AF: 0.750

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.750

Gnomad4 FIN exome AF: 0.318

Gnomad4 NFE exome AF: 0.342

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.386 AC: 58548 AN: 151796 Hom.: 11669 Cov.: 31 AF XY: 0.392 AC XY: 29085 AN XY: 74162

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.384

Gnomad4 EAS AF: 0.553

Gnomad4 SAS AF: 0.432

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.344

Alfa AF: 0.337 Hom.: 19154

Bravo AF: 0.387

Asia WGS AF: 0.481 AC: 1675 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.015
DANN	Benign	0.47

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17581368; hg19: chr8-21662445;