10-116126003-A-T

Position:

• chr10-116126003-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_005264.8(GFRA1):​c.434-446T>A variant causes a intron change. The variant allele was found at a frequency of 0.498 in 152,178 control chromosomes in the GnomAD database, including 20,171 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 0.50 (20171 hom., cov: 35)
• Consequence: GFRA1 NM_005264.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.43

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA1	NM_005264.8	c.434-446T>A		intron_variant		ENST00000355422.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA1	ENST00000355422.11	c.434-446T>A		intron_variant		5	NM_005264.8	A2

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75699 AN: 152060 Hom.: 20163 Cov.: 35

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.526

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

GnomAD4 genome AF: 0.498 AC: 75727 AN: 152178 Hom.: 20171 Cov.: 35 AF XY: 0.502 AC XY: 37310 AN XY: 74382

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.626

Gnomad4 ASJ AF: 0.562

Gnomad4 EAS AF: 0.572

Gnomad4 SAS AF: 0.560

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.561

Gnomad4 OTH AF: 0.527

Alfa AF: 0.402 Hom.: 1203

Bravo AF: 0.494

Asia WGS AF: 0.566 AC: 1964 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.82

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: rs952919; hg19: chr10-117885514;