rs7920934

Variant names:

• chr10-116202914-A-G
• rs7920934
• NM_005264.8:c.433+8717T>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+8717T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 151,928 control chromosomes in the GnomAD database, including 6,930 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 0.28 (6930 hom., cov: 32)
• Consequence: GFRA1 NM_005264.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.155
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 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.433+8717T>C		intron	N/A	NP_005255.1	P56159-1
	GFRA1	NM_001348098.4		c.433+8717T>C		intron	N/A	NP_001335027.1	P56159-1
	GFRA1	NM_001145453.4		c.418+66589T>C		intron	N/A	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.433+8717T>C		intron	N/A	ENSP00000347591.6	P56159-1
	GFRA1	ENST00000369236.5	TSL:1	c.418+66589T>C		intron	N/A	ENSP00000358239.1	P56159-2
	GFRA1	ENST00000369234.5	TSL:5	c.433+8717T>C		intron	N/A	ENSP00000358237.4	P56159-1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43209 AN: 151810 Hom.: 6917 Cov.: 32

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.285 AC: 43258 AN: 151928 Hom.: 6930 Cov.: 32 AF XY: 0.285 AC XY: 21156 AN XY: 74254

African (AFR) AF: 0.439 AC: 18153 AN: 41370

American (AMR) AF: 0.196 AC: 2995 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 701 AN: 3470

East Asian (EAS) AF: 0.146 AC: 751 AN: 5154

South Asian (SAS) AF: 0.276 AC: 1328 AN: 4812

European-Finnish (FIN) AF: 0.270 AC: 2852 AN: 10568

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15682 AN: 67958

Other (OTH) AF: 0.247 AC: 522 AN: 2110

Alfa AF: 0.260 Hom.: 1611

Bravo AF: 0.281

Asia WGS AF: 0.216 AC: 753 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.74
PhyloP100		-0.15
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: rs7920934; hg19: chr10-117962426;