8-21750589-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001495.5(GFRA2):​c.793C>T​(p.Arg265Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000252 in 1,588,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

GFRA2
NM_001495.5 missense, splice_region

Scores

11
7
1
Splicing: ADA: 0.02996
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.15
Variant links:
Genes affected
GFRA2 (HGNC:4244): (GDNF family receptor alpha 2) 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. The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This encoded protein acts preferentially as a receptor for NTN compared to its other family member, GDNF family receptor alpha 1. This gene is a candidate gene for RET-associated diseases. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GFRA2NM_001495.5 linkuse as main transcriptc.793C>T p.Arg265Trp missense_variant, splice_region_variant 4/9 ENST00000524240.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GFRA2ENST00000524240.6 linkuse as main transcriptc.793C>T p.Arg265Trp missense_variant, splice_region_variant 4/91 NM_001495.5 P1O00451-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152250
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000228
AC:
5
AN:
219546
Hom.:
0
AF XY:
0.0000167
AC XY:
2
AN XY:
119512
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000323
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000639
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000310
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000230
AC:
33
AN:
1436550
Hom.:
0
Cov.:
30
AF XY:
0.0000140
AC XY:
10
AN XY:
713280
show subpopulations
Gnomad4 AFR exome
AF:
0.0000303
Gnomad4 AMR exome
AF:
0.0000241
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000774
Gnomad4 SAS exome
AF:
0.0000119
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000192
Gnomad4 OTH exome
AF:
0.0000840
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152250
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000600
Hom.:
0
Bravo
AF:
0.0000529
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000118
AC:
1
ExAC
AF:
0.0000414
AC:
5

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 submitterclinical testingAmbry GeneticsAug 17, 2022The c.793C>T (p.R265W) alteration is located in exon 4 (coding exon 4) of the GFRA2 gene. This alteration results from a C to T substitution at nucleotide position 793, causing the arginine (R) at amino acid position 265 to be replaced by a tryptophan (W). 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
0.98
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.23
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.60
D;D;.;.
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
.;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Uncertain
0.016
D
MutationAssessor
Uncertain
2.8
M;M;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-7.1
D;D;D;D
REVEL
Pathogenic
0.70
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.97
MVP
0.82
MPC
1.8
ClinPred
0.92
D
GERP RS
3.9
Varity_R
0.90
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.030
dbscSNV1_RF
Benign
0.18
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.

Other links and lift over

dbSNP: rs375157617; hg19: chr8-21608101; API