chr10-116125439-G-C

Variant names:

• chr10-116125439-G-C
• rs2245020
• NM_005264.8:c.552C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005264.8(GFRA1):​c.552C>G​(p.Asn184Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N184S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GFRA1 NM_005264.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.282
• Publications: 26 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4177975).

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.552C>G	p.Asn184Lys	missense	Exon 6 of 11	NP_005255.1
	GFRA1	NM_001348098.4		c.552C>G	p.Asn184Lys	missense	Exon 6 of 11	NP_001335027.1
	GFRA1	NM_001145453.4		c.537C>G	p.Asn179Lys	missense	Exon 5 of 10	NP_001138925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.552C>G	p.Asn184Lys	missense	Exon 6 of 11	ENSP00000347591.6
	GFRA1	ENST00000369236.5	TSL:1	c.537C>G	p.Asn179Lys	missense	Exon 4 of 9	ENSP00000358239.1
	GFRA1	ENST00000369234.5	TSL:5	c.552C>G	p.Asn184Lys	missense	Exon 6 of 11	ENSP00000358237.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 34913

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.28
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.15
Sift	Benign	0.31	T
Sift4G	Benign	0.71	T
Polyphen		0.76	P
Vest4		0.47
MutPred		0.44		Gain of methylation at N184 (P = 0.0244)
MVP		0.47
MPC		0.48
ClinPred		0.36	T
GERP RS		-2.0
Varity_R		0.23
gMVP		0.50
Mutation Taster		=58/42	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: rs2245020; hg19: chr10-117884950;