rs45568534

Positions:

• chr10-116272222-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005264.8(GFRA1):​c.-193C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 628,662 control chromosomes in the GnomAD database, including 295 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 0.020 (46 hom., cov: 33)
  • Exomes 𝑓: 0.027 (249 hom.)
• Consequence: GFRA1 NM_005264.8 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93

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=-0.79).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0201 (3055/152320) while in subpopulation NFE AF= 0.0289 (1964/68026). AF 95% confidence interval is 0.0278. There are 46 homozygotes in gnomad4. There are 1440 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA1	NM_005264.8	c.-193C>G		5_prime_UTR_variant	2/11	ENST00000355422.11	NP_005255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422.11	c.-193C>G		5_prime_UTR_variant	2/11	5	NM_005264.8	ENSP00000347591	A2

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3055 AN: 152204 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0740

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00950

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0267 AC: 12730 AN: 476342 Hom.: 249 Cov.: 4 AF XY: 0.0263 AC XY: 6657 AN XY: 252842

Gnomad4 AFR exome AF: 0.00307

Gnomad4 AMR exome AF: 0.0168

Gnomad4 ASJ exome AF: 0.0824

Gnomad4 EAS exome AF: 0.0000319

Gnomad4 SAS exome AF: 0.0184

Gnomad4 FIN exome AF: 0.0146

Gnomad4 NFE exome AF: 0.0307

Gnomad4 OTH exome AF: 0.0329

GnomAD4 genome AF: 0.0201 AC: 3055 AN: 152320 Hom.: 46 Cov.: 33 AF XY: 0.0193 AC XY: 1440 AN XY: 74482

Gnomad4 AFR AF: 0.00447

Gnomad4 AMR AF: 0.0215

Gnomad4 ASJ AF: 0.0740

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.00950

Gnomad4 NFE AF: 0.0289

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0238 Hom.: 6

Bravo AF: 0.0214

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.7
DANN	Benign	0.79

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: rs45568534; hg19: chr10-118031734;