chr10-116065607-T-G

Variant names:

• chr10-116065607-T-G
• rs769034000
• NM_005264.8:c.1217A>C

Variant summary

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

The NM_005264.8(GFRA1):​c.1217A>C​(p.Asn406Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFRA1 NM_005264.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63
• 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: 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=0.33275953).

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.1217A>C	p.Asn406Thr	missense	Exon 10 of 11	NP_005255.1	P56159-1
	GFRA1	NM_001348098.4		c.1217A>C	p.Asn406Thr	missense	Exon 10 of 11	NP_001335027.1	P56159-1
	GFRA1	NM_001145453.4		c.1202A>C	p.Asn401Thr	missense	Exon 9 of 10	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.1217A>C	p.Asn406Thr	missense	Exon 10 of 11	ENSP00000347591.6	P56159-1
	GFRA1	ENST00000369236.5	TSL:1	c.1202A>C	p.Asn401Thr	missense	Exon 8 of 9	ENSP00000358239.1	P56159-2
	GFRA1	ENST00000369234.5	TSL:5	c.1217A>C	p.Asn406Thr	missense	Exon 10 of 11	ENSP00000358237.4	P56159-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.14
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.010	D
Polyphen		0.94	P
Vest4		0.65
MutPred		0.30		Loss of catalytic residue at N406 (P = 0.0357)
MVP		0.81
MPC		0.97
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.32
gMVP		0.68
Mutation Taster		=55/45	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: rs769034000; hg19: chr10-117825118;