chr5-138254089-G-T

Position:

• chr5-138254089-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001496.4(GFRA3):​c.857C>A​(p.Ser286Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,362 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GFRA3 NM_001496.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

Genes affected

GFRA3 (HGNC:4245): (GDNF family receptor alpha 3) The protein encoded by this gene is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor and a member of the GDNF receptor family. It forms a signaling receptor complex with RET tyrosine kinase receptor and binds the ligand, artemin. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA3	NM_001496.4	c.857C>A	p.Ser286Tyr	missense_variant	5/8	ENST00000274721.8	NP_001487.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA3	ENST00000274721.8	c.857C>A	p.Ser286Tyr	missense_variant	5/8	1	NM_001496.4	ENSP00000274721	P2
GFRA3	ENST00000378362.3	c.764C>A	p.Ser255Tyr	missense_variant	4/7	1		ENSP00000367613	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460362 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726618

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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, 2024

The c.857C>A (p.S286Y) alteration is located in exon 5 (coding exon 5) of the GFRA3 gene. This alteration results from a C to A substitution at nucleotide position 857, causing the serine (S) at amino acid position 286 to be replaced by a tyrosine (Y). 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	0.16
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.74
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.67	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.2	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.85	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.95	P;D
Vest4		0.49
MutPred		0.63		Gain of helix (P = 0.0854);.;
MVP		0.83
MPC		2.4
ClinPred		0.71	D
GERP RS		3.5
Varity_R		0.11
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-137589778;