chr8-21727549-G-C

Variant names:

• chr8-21727549-G-C
• rs4739217
• NM_001495.5:c.795-21508C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001495.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA2	NM_001495.5	MANE Select	c.795-21508C>G		intron	N/A	NP_001486.4
	GFRA2	NM_001165038.2		c.480-21508C>G		intron	N/A	NP_001158510.1	O00451-3
	GFRA2	NM_001165039.2		c.396-21508C>G		intron	N/A	NP_001158511.1	O00451-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA2	ENST00000524240.6	TSL:1 MANE Select	c.795-21508C>G		intron	N/A	ENSP00000428518.1	O00451-1
	GFRA2	ENST00000517892.5	TSL:1	c.480-21508C>G		intron	N/A	ENSP00000429979.1	O00451-3
	GFRA2	ENST00000518077.5	TSL:1	c.396-21508C>G		intron	N/A	ENSP00000429206.1	O00451-2

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

African (AFR) AF: 0.108 AC: 4496 AN: 41532

American (AMR) AF: 0.554 AC: 8468 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1471 AN: 3468

East Asian (EAS) AF: 0.610 AC: 3141 AN: 5150

South Asian (SAS) AF: 0.464 AC: 2233 AN: 4810

European-Finnish (FIN) AF: 0.554 AC: 5875 AN: 10608

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.491 AC: 33362 AN: 67962

Other (OTH) AF: 0.416 AC: 877 AN: 2110

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.61
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4739217; hg19: chr8-21585061;