Variant chr8-21693346-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001495.5(GFRA2):c.1327C>T(p.Pro443Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,613,242 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0028 ( 9 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 76 hom. )

Consequence

GFRA2
NM_001495.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.215

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]

GFRA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016376376).

BP6

Variant 8-21693346-G-A is Benign according to our data. Variant chr8-21693346-G-A is described in ClinVar as [Benign]. Clinvar id is 708036.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA2	NM_001495.5 linkuse as main transcript	c.1327C>T	p.Pro443Ser	missense_variant	9/9	ENST00000524240.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA2	ENST00000524240.6 linkuse as main transcript	c.1327C>T	p.Pro443Ser	missense_variant	9/9	1	NM_001495.5	P1	O00451-1

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

428

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0590

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.00434

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00640

AC:

1574

AN:

246126

Hom.:

AF XY:

0.00602

AC XY:

805

AN XY:

133780

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.0000584

Gnomad ASJ exome

AF:

0.000798

Gnomad EAS exome

AF:

0.0714

Gnomad SAS exome

AF:

0.00302

Gnomad FIN exome

AF:

0.00427

Gnomad NFE exome

AF:

0.000733

Gnomad OTH exome

AF:

0.00316

GnomAD4 exome

AF:

0.00226

AC:

3308

AN:

1461048

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

1735

AN XY:

726778

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000896

Gnomad4 ASJ exome

AF:

0.000765

Gnomad4 EAS exome

AF:

0.0557

Gnomad4 SAS exome

AF:

0.00304

Gnomad4 FIN exome

AF:

0.00532

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.00297

GnomAD4 genome

AF:

0.00281

AC:

428

AN:

152194

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.0587

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.00434

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00295

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00615

AC:

743

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.43

DEOGEN2

Benign

0.061

T;T;.;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.26

MetaRNN

Benign

0.0016

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.83

N;N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.60

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.45

T;T;T;T

Sift4G

Benign

0.93

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.036

MVP

0.28

MPC

0.021

ClinPred

0.0035

GERP RS

1.2

Varity_R

0.023

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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