chr10-116218138-C-T

Variant names:

• chr10-116218138-C-T
• rs4562724
• NM_005264.8:c.419-6493G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005264.8(GFRA1):​c.419-6493G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 151,962 control chromosomes in the GnomAD database, including 13,345 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 (13345 hom., cov: 32)
• Consequence: GFRA1 NM_005264.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.525
• Publications: 3 publications found

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]

GFRA1 Gene-Disease associations (from GenCC):

• renal hypodysplasia/aplasia 4

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFRA1	NM_005264.8	c.419-6493G>A		intron_variant	Intron 4 of 10	ENST00000355422.11	NP_005255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422.11	c.419-6493G>A		intron_variant	Intron 4 of 10	5	NM_005264.8	ENSP00000347591.6

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61155 AN: 151844 Hom.: 13338 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.408

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

GnomAD4 genome AF: 0.403 AC: 61167 AN: 151962 Hom.: 13345 Cov.: 32 AF XY: 0.402 AC XY: 29850 AN XY: 74248

African (AFR) AF: 0.224 AC: 9271 AN: 41458

American (AMR) AF: 0.504 AC: 7701 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1307 AN: 3472

East Asian (EAS) AF: 0.551 AC: 2829 AN: 5134

South Asian (SAS) AF: 0.293 AC: 1410 AN: 4806

European-Finnish (FIN) AF: 0.467 AC: 4918 AN: 10540

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32289 AN: 67966

Other (OTH) AF: 0.409 AC: 862 AN: 2106

Alfa AF: 0.334 Hom.: 1608

Bravo AF: 0.405

Asia WGS AF: 0.389 AC: 1353 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.55
DANN	Benign	0.54
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4562724; hg19: chr10-117977650;