Variant chr5-138259590-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001496.4(GFRA3):c.439A>G(p.Met147Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,568,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

GFRA3
NM_001496.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.256

Variant links:

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]

GFRA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024943084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA3	NM_001496.4 linkuse as main transcript	c.439A>G	p.Met147Val	missense_variant	3/8	ENST00000274721.8	NP_001487.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA3	ENST00000274721.8 linkuse as main transcript	c.439A>G	p.Met147Val	missense_variant	3/8	1	NM_001496.4	ENSP00000274721	P2	O60609-1
GFRA3	ENST00000378362.3 linkuse as main transcript	c.380-1639A>G		intron_variant		1		ENSP00000367613	A2	O60609-2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000954

AC:

AN:

251490

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1416376

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

707740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000633

Gnomad4 SAS exome

AF:

0.000387

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.34e-7

Gnomad4 OTH exome

AF:

0.000102

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000123

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2024

The c.439A>G (p.M147V) alteration is located in exon 3 (coding exon 3) of the GFRA3 gene. This alteration results from a A to G substitution at nucleotide position 439, causing the methionine (M) at amino acid position 147 to be replaced by a valine (V). 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

0.097

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.15

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.70

M_CAP

Benign

0.0042

MetaRNN

Benign

0.025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.80

REVEL

Benign

0.027

Sift

Benign

0.32

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.11

MutPred

0.38

Gain of methylation at K146 (P = 0.0173);

MVP

0.37

MPC

1.1

ClinPred

0.014

GERP RS

1.4

Varity_R

0.057

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over