8-21723708-T-C

Position:

• chr8-21723708-T-C

Variant summary

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

The NM_001495.5(GFRA2):​c.795-17667A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 151,986 control chromosomes in the GnomAD database, including 15,054 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 0.40 (15054 hom., cov: 32)
• Consequence: GFRA2 NM_001495.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA2	NM_001495.5	c.795-17667A>G		intron_variant		ENST00000524240.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA2	ENST00000524240.6	c.795-17667A>G		intron_variant		1	NM_001495.5	P1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61291 AN: 151868 Hom.: 15009 Cov.: 32

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.377

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

GnomAD4 genome AF: 0.404 AC: 61390 AN: 151986 Hom.: 15054 Cov.: 32 AF XY: 0.400 AC XY: 29743 AN XY: 74292

Gnomad4 AFR AF: 0.698

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.299

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.301

Gnomad4 OTH AF: 0.376

Alfa AF: 0.271 Hom.: 1265

Bravo AF: 0.408

Asia WGS AF: 0.308 AC: 1070 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.091
DANN	Benign	0.32

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: rs6587002; hg19: chr8-21581220;