8-21804933-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000517328.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA2	ENST00000517328.5	TSL:5	c.-36+84G>T		intron	N/A	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

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 0.750 AC: 3 AN: 4

European-Finnish (FIN) AF: 0.318 AC: 7 AN: 22

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.342 AC: 13 AN: 38

Other (OTH) AF: 0.400 AC: 4 AN: 10

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

African (AFR) AF: 0.433 AC: 17890 AN: 41346

American (AMR) AF: 0.423 AC: 6447 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1330 AN: 3468

East Asian (EAS) AF: 0.553 AC: 2843 AN: 5140

South Asian (SAS) AF: 0.432 AC: 2078 AN: 4808

European-Finnish (FIN) AF: 0.388 AC: 4093 AN: 10558

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22706 AN: 67918

Other (OTH) AF: 0.344 AC: 722 AN: 2100

Alfa AF: 0.348 Hom.: 41293

Bravo AF: 0.387

Asia WGS AF: 0.481 AC: 1675 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.015
DANN	Benign	0.47
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs17581368; hg19: chr8-21662445;