rs11197557

Variant names:

• chr10-116158555-C-T
• rs11197557
• NM_005264.8:c.434-32998G>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.434-32998G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,096 control chromosomes in the GnomAD database, including 2,924 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 0.18 (2924 hom., cov: 33)
• Consequence: GFRA1 NM_005264.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.507
• Publications: 4 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.279 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	NM_005264.8	MANE Select	c.434-32998G>A		intron	N/A	NP_005255.1
	GFRA1	NM_001348098.4		c.434-32998G>A		intron	N/A	NP_001335027.1
	GFRA1	NM_001145453.4		c.419-32998G>A		intron	N/A	NP_001138925.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.434-32998G>A		intron	N/A	ENSP00000347591.6
	GFRA1	ENST00000369236.5	TSL:1	c.419-32998G>A		intron	N/A	ENSP00000358239.1
	GFRA1	ENST00000369234.5	TSL:5	c.434-32998G>A		intron	N/A	ENSP00000358237.4

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26722 AN: 151980 Hom.: 2921 Cov.: 33

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.188

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

GnomAD4 genome AF: 0.176 AC: 26730 AN: 152096 Hom.: 2924 Cov.: 33 AF XY: 0.180 AC XY: 13355 AN XY: 74346

African (AFR) AF: 0.0418 AC: 1734 AN: 41502

American (AMR) AF: 0.286 AC: 4374 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 726 AN: 3464

East Asian (EAS) AF: 0.258 AC: 1331 AN: 5160

South Asian (SAS) AF: 0.251 AC: 1209 AN: 4816

European-Finnish (FIN) AF: 0.206 AC: 2175 AN: 10566

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14598 AN: 67994

Other (OTH) AF: 0.187 AC: 394 AN: 2112

Alfa AF: 0.205 Hom.: 4807

Bravo AF: 0.178

Asia WGS AF: 0.217 AC: 753 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.0
DANN	Benign	0.38
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: rs11197557; hg19: chr10-117918067;