rs11197571

Variant names:

• chr10-116183122-A-G
• rs11197571
• NM_005264.8:c.433+28509T>C

Variant summary

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

The NM_005264.8(GFRA1):​c.433+28509T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 152,274 control chromosomes in the GnomAD database, including 1,386 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 0.13 (1386 hom., cov: 33)
• Consequence: GFRA1 NM_005264.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.60
• Publications: 6 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 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.433+28509T>C		intron	N/A	NP_005255.1
	GFRA1	NM_001348098.4		c.433+28509T>C		intron	N/A	NP_001335027.1
	GFRA1	NM_001145453.4		c.419-57565T>C		intron	N/A	NP_001138925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.433+28509T>C		intron	N/A	ENSP00000347591.6
	GFRA1	ENST00000369236.5	TSL:1	c.419-57565T>C		intron	N/A	ENSP00000358239.1
	GFRA1	ENST00000369234.5	TSL:5	c.433+28509T>C		intron	N/A	ENSP00000358237.4

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20207 AN: 152156 Hom.: 1380 Cov.: 33

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.0599

Gnomad SAS AF: 0.0751

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.142

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

GnomAD4 genome AF: 0.133 AC: 20236 AN: 152274 Hom.: 1386 Cov.: 33 AF XY: 0.130 AC XY: 9656 AN XY: 74452

African (AFR) AF: 0.117 AC: 4861 AN: 41546

American (AMR) AF: 0.111 AC: 1703 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 561 AN: 3470

East Asian (EAS) AF: 0.0597 AC: 309 AN: 5176

South Asian (SAS) AF: 0.0748 AC: 361 AN: 4828

European-Finnish (FIN) AF: 0.126 AC: 1343 AN: 10618

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10634 AN: 68026

Other (OTH) AF: 0.142 AC: 300 AN: 2108

Alfa AF: 0.147 Hom.: 5053

Bravo AF: 0.129

Asia WGS AF: 0.0770 AC: 267 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.61
PhyloP100		2.6
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: rs11197571; hg19: chr10-117942634;