rs11197557

Positions:

• chr10-116158555-C-T

Variant summary

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

The NM_005264.8(GFRA1):​c.434-32998G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,096 control chromosomes in the GnomAD database, including 2,924 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 0.18 (2924 hom., cov: 33)
• Consequence: GFRA1 NM_005264.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.507

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA1	NM_005264.8	c.434-32998G>A		intron_variant		ENST00000355422.11	NP_005255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422.11	c.434-32998G>A		intron_variant		5	NM_005264.8	ENSP00000347591.6

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26722 AN: 151980 Hom.: 2921 Cov.: 33

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.188

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

GnomAD4 genome AF: 0.176 AC: 26730 AN: 152096 Hom.: 2924 Cov.: 33 AF XY: 0.180 AC XY: 13355 AN XY: 74346

Gnomad4 AFR AF: 0.0418

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.206

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.187

Alfa AF: 0.210 Hom.: 3328

Bravo AF: 0.178

Asia WGS AF: 0.217 AC: 753 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.0
DANN	Benign	0.38

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: rs11197557; hg19: chr10-117918067;