rs180552

Positions:

• chr10-116059331-G-A
• chr10-116059331-G-C
• chr10-116059331-G-T

Variant summary

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

The NM_005264.8(GFRA1):​c.*5067C>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 0.39 in 152,036 control chromosomes in the GnomAD database, including 14,014 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 0.39 (14012 hom., cov: 33)
  • Exomes 𝑓: 0.19 (2 hom.)
• Consequence: GFRA1 NM_005264.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.147

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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA1	NM_005264.8	c.*5067C>T		3_prime_UTR_variant	11/11	ENST00000355422.11	NP_005255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422	c.*5067C>T		3_prime_UTR_variant	11/11	5	NM_005264.8	ENSP00000347591.6
GFRA1	ENST00000369236	c.*5067C>T		3_prime_UTR_variant	9/9	1		ENSP00000358239.1

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59241 AN: 151896 Hom.: 13972 Cov.: 33

Gnomad AFR AF: 0.653

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.390

GnomAD4 exome AF: 0.192 AC: 5 AN: 26 Hom.: 2 Cov.: 0 AF XY: 0.111 AC XY: 2 AN XY: 18

Gnomad4 AFR exome AF: 1.00

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.390 AC: 59326 AN: 152010 Hom.: 14012 Cov.: 33 AF XY: 0.391 AC XY: 29029 AN XY: 74320

Gnomad4 AFR AF: 0.653

Gnomad4 AMR AF: 0.351

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.613

Gnomad4 SAS AF: 0.337

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.391

Alfa AF: 0.278 Hom.: 8547

Bravo AF: 0.409

Asia WGS AF: 0.482 AC: 1675 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs180552; hg19: chr10-117818842;