10-116065607-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity GFRA1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33275953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFRA1	NM_005264.8	c.1217A>C	p.Asn406Thr	missense_variant	Exon 10 of 11	ENST00000355422.11	NP_005255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422.11	c.1217A>C	p.Asn406Thr	missense_variant	Exon 10 of 11	5	NM_005264.8	ENSP00000347591.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1217A>C (p.N406T) alteration is located in exon 10 (coding exon 9) of the GFRA1 gene. This alteration results from a A to C substitution at nucleotide position 1217, causing the asparagine (N) at amino acid position 406 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	.;T;.;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.7	.;.;M;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D;.;.;.
REVEL	Benign	0.14
Sift	Uncertain	0.0060	D;.;.;.
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.94	P;P;P;P
Vest4		0.65
MutPred		0.30		.;.;Loss of catalytic residue at N406 (P = 0.0357);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs769034000; hg19: chr10-117825118;