rs180554

chr10-116059049-G-Achr10-116059049-G-Cchr10-116059049-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.*5349C>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 0.404 in 152,064 control chromosomes in the GnomAD database, including 15,326 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 (15324 hom., cov: 32)
  • Exomes 𝑓: 0.36 (2 hom.)
• Consequence: GFRA1 NM_005264.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.08

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA1	NM_005264.8	c.*5349C>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.*5349C>T		3_prime_UTR_variant	11/11	5	NM_005264.8	A2
GFRA1	ENST00000369236.5	c.*5349C>T		3_prime_UTR_variant	9/9	1		P4

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61343 AN: 151924 Hom.: 15285 Cov.: 32

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.403

GnomAD4 exome AF: 0.364 AC: 8 AN: 22 Hom.: 2 Cov.: 0 AF XY: 0.375 AC XY: 6 AN XY: 16

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.350

GnomAD4 genome AF: 0.404 AC: 61429 AN: 152042 Hom.: 15324 Cov.: 32 AF XY: 0.405 AC XY: 30074 AN XY: 74320

Gnomad4 AFR AF: 0.695

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.616

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.283

Gnomad4 NFE AF: 0.257

Gnomad4 OTH AF: 0.404

Alfa AF: 0.285 Hom.: 6288

Bravo AF: 0.424

Asia WGS AF: 0.488 AC: 1694 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.016
Dann	Benign	0.58

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: rs180554; hg19: chr10-117818560; COSMIC: COSV62609897; COSMIC: COSV62609897;