8-21727549-G-C

Position:

• chr8-21727549-G-C

Variant summary

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

The NM_001495.5(GFRA2):​c.795-21508C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 152,136 control chromosomes in the GnomAD database, including 14,689 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 (14689 hom., cov: 32)
• Consequence: GFRA2 NM_001495.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.399

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA2	NM_001495.5	c.795-21508C>G		intron_variant		ENST00000524240.6	NP_001486.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA2	ENST00000524240.6	c.795-21508C>G		intron_variant		1	NM_001495.5	ENSP00000428518	P1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60311 AN: 152018 Hom.: 14689 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.419

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

GnomAD4 genome AF: 0.396 AC: 60308 AN: 152136 Hom.: 14689 Cov.: 32 AF XY: 0.404 AC XY: 30024 AN XY: 74364

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.610

Gnomad4 SAS AF: 0.464

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.491

Gnomad4 OTH AF: 0.416

Alfa AF: 0.440 Hom.: 2092

Bravo AF: 0.386

Asia WGS AF: 0.486 AC: 1690 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.61

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: rs4739217; hg19: chr8-21585061;