10-116096759-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005264.8(GFRA1):c.776G>A(p.Arg259His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,438,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: GFRA1 NM_005264.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA1	NM_005264.8	c.776G>A	p.Arg259His	missense_variant	7/11	ENST00000355422.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA1	ENST00000355422.11	c.776G>A	p.Arg259His	missense_variant	7/11	5	NM_005264.8	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1438352 Hom.: 0 Cov.: 27 AF XY: 0.00000279 AC XY: 2 AN XY: 717256

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000458

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2022

The c.776G>A (p.R259H) alteration is located in exon 7 (coding exon 6) of the GFRA1 gene. This alteration results from a G to A substitution at nucleotide position 776, causing the arginine (R) at amino acid position 259 to be replaced by a histidine (H). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.7	D;.;.;.
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.92
MutPred		0.78		.;.;Loss of disorder (P = 0.0644);Loss of disorder (P = 0.0644);
MVP		0.88
MPC		1.3
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.78
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1184814248; hg19: chr10-117856270; COSMIC: COSV105274642;