chr5-138257913-G-A

Position:

• chr5-138257913-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001496.4(GFRA3):​c.511C>T​(p.Leu171Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000034 (0 hom.)
• Consequence: GFRA3 NM_001496.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.908

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24550879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA3	NM_001496.4	c.511C>T	p.Leu171Phe	missense_variant	4/8	ENST00000274721.8	NP_001487.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA3	ENST00000274721.8	c.511C>T	p.Leu171Phe	missense_variant	4/8	1	NM_001496.4	ENSP00000274721	P2
GFRA3	ENST00000378362.3	c.418C>T	p.Leu140Phe	missense_variant	3/7	1		ENSP00000367613	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

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: 0.00000450

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

Jun 05, 2024

The c.511C>T (p.L171F) alteration is located in exon 4 (coding exon 4) of the GFRA3 gene. This alteration results from a C to T substitution at nucleotide position 511, causing the leucine (L) at amino acid position 171 to be replaced by a phenylalanine (F). 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	0.15
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.89	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.29
Sift	Benign	0.032	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.068	B;D
Vest4		0.23
MutPred		0.71		Loss of ubiquitination at K174 (P = 0.1612);.;
MVP		0.76
MPC		1.7
ClinPred		0.86	D
GERP RS		3.3
Varity_R		0.25
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-137593602;