rs45568534

Variant names:

• chr10-116272222-G-C
• rs45568534
• NM_005264.8:c.-193C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005264.8(GFRA1):​c.-193C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 628,662 control chromosomes in the GnomAD database, including 295 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 0.020 (46 hom., cov: 33)
  • Exomes 𝑓: 0.027 (249 hom.)
• Consequence: GFRA1 NM_005264.8 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 11 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=-0.79).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0201 (3055/152320) while in subpopulation NFE AF = 0.0289 (1964/68026). AF 95% confidence interval is 0.0278. There are 46 homozygotes in GnomAd4. There are 1440 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	NM_005264.8	MANE Select	c.-193C>G		5_prime_UTR	Exon 2 of 11	NP_005255.1	P56159-1
	GFRA1	NM_001348098.4		c.-193C>G		5_prime_UTR	Exon 2 of 11	NP_001335027.1	P56159-1
	GFRA1	NM_001145453.4		c.-193C>G		5_prime_UTR	Exon 2 of 10	NP_001138925.1	P56159-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.-193C>G		5_prime_UTR	Exon 2 of 11	ENSP00000347591.6	P56159-1
	GFRA1	ENST00000369236.5	TSL:1	c.-193C>G		5_prime_UTR	Exon 1 of 9	ENSP00000358239.1	P56159-2
	GFRA1	ENST00000369234.5	TSL:5	c.-193C>G		5_prime_UTR	Exon 2 of 11	ENSP00000358237.4	P56159-1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3055 AN: 152204 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0740

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00950

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0267 AC: 12730 AN: 476342 Hom.: 249 Cov.: 4 AF XY: 0.0263 AC XY: 6657 AN XY: 252842

African (AFR) AF: 0.00307 AC: 40 AN: 13038

American (AMR) AF: 0.0168 AC: 375 AN: 22292

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 1210 AN: 14678

East Asian (EAS) AF: 0.0000319 AC: 1 AN: 31318

South Asian (SAS) AF: 0.0184 AC: 883 AN: 48030

European-Finnish (FIN) AF: 0.0146 AC: 480 AN: 32802

Middle Eastern (MID) AF: 0.0459 AC: 94 AN: 2048

European-Non Finnish (NFE) AF: 0.0307 AC: 8760 AN: 285152

Other (OTH) AF: 0.0329 AC: 887 AN: 26984

GnomAD4 genome AF: 0.0201 AC: 3055 AN: 152320 Hom.: 46 Cov.: 33 AF XY: 0.0193 AC XY: 1440 AN XY: 74482

African (AFR) AF: 0.00447 AC: 186 AN: 41582

American (AMR) AF: 0.0215 AC: 329 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0740 AC: 257 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4830

European-Finnish (FIN) AF: 0.00950 AC: 101 AN: 10628

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0289 AC: 1964 AN: 68026

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.0238 Hom.: 6

Bravo AF: 0.0214

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.7
DANN	Benign	0.79
PhyloP100		-1.9
PromoterAI		0.10	Neutral
Mutation Taster		=300/0	polymorphism

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: rs45568534; hg19: chr10-118031734;