8-21742957-T-C

Variant names:

• chr8-21742957-T-C
• rs6988470
• NM_001495.5:c.794+7631A>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.794+7631A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 152,146 control chromosomes in the GnomAD database, including 27,422 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 0.57 (27422 hom., cov: 33)
• Consequence: GFRA2 NM_001495.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.184
• Publications: 4 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 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.794+7631A>G		intron	N/A	NP_001486.4
	GFRA2	NM_001165038.2		c.479+7631A>G		intron	N/A	NP_001158510.1	O00451-3
	GFRA2	NM_001165039.2		c.395+7631A>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.794+7631A>G		intron	N/A	ENSP00000428518.1	O00451-1
	GFRA2	ENST00000517892.5	TSL:1	c.479+7631A>G		intron	N/A	ENSP00000429979.1	O00451-3
	GFRA2	ENST00000518077.5	TSL:1	c.395+7631A>G		intron	N/A	ENSP00000429206.1	O00451-2

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86698 AN: 152028 Hom.: 27359 Cov.: 33

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.532

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

GnomAD4 genome AF: 0.571 AC: 86808 AN: 152146 Hom.: 27422 Cov.: 33 AF XY: 0.566 AC XY: 42129 AN XY: 74376

African (AFR) AF: 0.864 AC: 35911 AN: 41546

American (AMR) AF: 0.412 AC: 6302 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1953 AN: 3466

East Asian (EAS) AF: 0.425 AC: 2196 AN: 5166

South Asian (SAS) AF: 0.451 AC: 2177 AN: 4822

European-Finnish (FIN) AF: 0.472 AC: 4981 AN: 10564

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31603 AN: 67978

Other (OTH) AF: 0.534 AC: 1127 AN: 2110

Alfa AF: 0.554 Hom.: 5787

Bravo AF: 0.576

Asia WGS AF: 0.493 AC: 1715 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.63
DANN	Benign	0.54
PhyloP100		-0.18
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: rs6988470; hg19: chr8-21600469;