10-116179856-G-C

Variant names:

• chr10-116179856-G-C
• rs12762746
• NM_005264.8:c.433+31775C>G

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+31775C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 151,908 control chromosomes in the GnomAD database, including 23,566 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 0.55 (23566 hom., cov: 31)
• Consequence: GFRA1 NM_005264.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.111
• Publications: 1 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.586 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+31775C>G		intron	N/A	NP_005255.1
	GFRA1	NM_001348098.4		c.433+31775C>G		intron	N/A	NP_001335027.1
	GFRA1	NM_001145453.4		c.419-54299C>G		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+31775C>G		intron	N/A	ENSP00000347591.6
	GFRA1	ENST00000369236.5	TSL:1	c.419-54299C>G		intron	N/A	ENSP00000358239.1
	GFRA1	ENST00000369234.5	TSL:5	c.433+31775C>G		intron	N/A	ENSP00000358237.4

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84266 AN: 151790 Hom.: 23575 Cov.: 31

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.699

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.556

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

GnomAD4 genome AF: 0.555 AC: 84273 AN: 151908 Hom.: 23566 Cov.: 31 AF XY: 0.555 AC XY: 41168 AN XY: 74218

African (AFR) AF: 0.468 AC: 19365 AN: 41422

American (AMR) AF: 0.554 AC: 8458 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2192 AN: 3468

East Asian (EAS) AF: 0.584 AC: 3000 AN: 5136

South Asian (SAS) AF: 0.539 AC: 2586 AN: 4798

European-Finnish (FIN) AF: 0.616 AC: 6507 AN: 10566

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.591 AC: 40162 AN: 67944

Other (OTH) AF: 0.556 AC: 1172 AN: 2108

Alfa AF: 0.568 Hom.: 2930

Bravo AF: 0.549

Asia WGS AF: 0.564 AC: 1960 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.5
DANN	Benign	0.49
PhyloP100		0.11
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: rs12762746; hg19: chr10-117939368;