rs1679568

Variant names:

• chr10-116058040-G-A
• rs1679568
• NM_005264.8:c.*6358C>T

Variant summary

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

The NM_005264.8(GFRA1):​c.*6358C>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 0.224 in 141,356 control chromosomes in the GnomAD database, including 3,971 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 0.23 (3965 hom., cov: 29)
  • Exomes 𝑓: 0.038 (6 hom.)
• Consequence: GFRA1 NM_005264.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508
• Publications: 7 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005264.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	NM_005264.8	MANE Select	c.*6358C>T		3_prime_UTR	Exon 11 of 11	NP_005255.1
	GFRA1	NM_001348098.4		c.*6358C>T		3_prime_UTR	Exon 11 of 11	NP_001335027.1
	GFRA1	NM_001145453.4		c.*6358C>T		3_prime_UTR	Exon 10 of 10	NP_001138925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.*6358C>T		3_prime_UTR	Exon 11 of 11	ENSP00000347591.6
	GFRA1	ENST00000369236.5	TSL:1	c.*6358C>T		3_prime_UTR	Exon 9 of 9	ENSP00000358239.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 31617 AN: 140252 Hom.: 3958 Cov.: 29

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.243

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.0377 AC: 38 AN: 1008 Hom.: 6 Cov.: 0 AF XY: 0.0364 AC XY: 28 AN XY: 770

African (AFR) AF: 0.0714 AC: 1 AN: 14

American (AMR) AF: 0.0500 AC: 1 AN: 20

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10

East Asian (EAS) AF: 0.0625 AC: 2 AN: 32

South Asian (SAS) AF: 0.00 AC: 0 AN: 16

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.0371 AC: 32 AN: 862

Other (OTH) AF: 0.0500 AC: 2 AN: 40

GnomAD4 genome AF: 0.226 AC: 31653 AN: 140348 Hom.: 3965 Cov.: 29 AF XY: 0.223 AC XY: 15218 AN XY: 68214

African (AFR) AF: 0.346 AC: 12948 AN: 37476

American (AMR) AF: 0.169 AC: 2346 AN: 13912

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 496 AN: 3200

East Asian (EAS) AF: 0.173 AC: 648 AN: 3736

South Asian (SAS) AF: 0.166 AC: 714 AN: 4310

European-Finnish (FIN) AF: 0.191 AC: 1859 AN: 9744

Middle Eastern (MID) AF: 0.243 AC: 66 AN: 272

European-Non Finnish (NFE) AF: 0.185 AC: 12010 AN: 64846

Other (OTH) AF: 0.230 AC: 448 AN: 1952

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.85
DANN	Benign	0.45
PhyloP100		0.51
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: rs1679568; hg19: chr10-117817551;