rs1679568

chr10-116058040-G-A

Variant summary

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

The NM_005264.8(GFRA1):c.*6358C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 141,356 control chromosomes in the GnomAD database, including 3,971 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 0.23 (3965 hom., cov: 29)
  • Exomes 𝑓: 0.038 (6 hom.)
• Consequence: GFRA1 NM_005264.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508

Genes affected

GFRA1 (HGNC:4243): (GDNF family receptor alpha 1) This gene encodes a member of the glial cell line-derived neurotrophic factor receptor (GDNFR) family of proteins. The encoded preproprotein is proteolytically processed to generate the mature receptor. 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. This receptor is a glycosylphosphatidylinositol (GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for Hirschsprung disease. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA1	NM_005264.8	c.*6358C>T		3_prime_UTR_variant	11/11	ENST00000355422.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA1	ENST00000355422.11	c.*6358C>T		3_prime_UTR_variant	11/11	5	NM_005264.8	A2
GFRA1	ENST00000369236.5	c.*6358C>T		3_prime_UTR_variant	9/9	1		P4

Frequencies

GnomAD3 genomes AF: 0.225 AC: 31617 AN: 140252 Hom.: 3958 Cov.: 29

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.243

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.0377 AC: 38 AN: 1008 Hom.: 6 Cov.: 0 AF XY: 0.0364 AC XY: 28 AN XY: 770

Gnomad4 AFR exome AF: 0.0714

Gnomad4 AMR exome AF: 0.0500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0625

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0371

Gnomad4 OTH exome AF: 0.0500

GnomAD4 genome AF: 0.226 AC: 31653 AN: 140348 Hom.: 3965 Cov.: 29 AF XY: 0.223 AC XY: 15218 AN XY: 68214

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.230

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.85
Dann	Benign	0.45

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: rs1679568; hg19: chr10-117817551;