Genetic Variant NM_001495.5:c.1385T>A (chr8-21693288-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001495.5(GFRA2):c.1385T>A(p.Leu462Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,610,344 control chromosomes in the GnomAD database, including 128,185 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.38 ( 11078 hom., cov: 31)

Exomes 𝑓: 0.40 ( 117107 hom. )

Consequence

GFRA2
NM_001495.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.34

Publications

26 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031813085).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFRA2	NM_001495.5 link	c.1385T>A	p.Leu462Gln	missense_variant	Exon 9 of 9	ENST00000524240.6	NP_001486.4	O00451-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFRA2	ENST00000524240.6 link	c.1385T>A	p.Leu462Gln	missense_variant	Exon 9 of 9	1	NM_001495.5	ENSP00000428518.1		O00451-1

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

57331

AN:

151770

Hom.:

11063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.343

Gnomad AMI

AF:

0.440

Gnomad AMR

AF:

0.324

Gnomad ASJ

AF:

0.424

Gnomad EAS

AF:

0.440

Gnomad SAS

AF:

0.370

Gnomad FIN

AF:

0.327

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.411

Gnomad OTH

AF:

0.387

GnomAD2 exomes

AF:

0.382

AC:

93634

AN:

245262

AF XY:

0.387

show subpopulations

Gnomad AFR exome

AF:

0.336

Gnomad AMR exome

AF:

0.289

Gnomad ASJ exome

AF:

0.444

Gnomad EAS exome

AF:

0.446

Gnomad FIN exome

AF:

0.337

Gnomad NFE exome

AF:

0.406

Gnomad OTH exome

AF:

0.401

GnomAD4 exome

AF:

0.399

AC:

581374

AN:

1458454

Hom.:

117107

Cov.:

AF XY:

0.400

AC XY:

289891

AN XY:

725246

show subpopulations

African (AFR)

AF:

0.335

AC:

11180

AN:

33376

American (AMR)

AF:

0.295

AC:

13077

AN:

44326

Ashkenazi Jewish (ASJ)

AF:

0.437

AC:

11383

AN:

26056

East Asian (EAS)

AF:

0.444

AC:

17542

AN:

39538

South Asian (SAS)

AF:

0.387

AC:

33250

AN:

85838

European-Finnish (FIN)

AF:

0.345

AC:

18391

AN:

53308

Middle Eastern (MID)

AF:

0.426

AC:

2454

AN:

5754

European-Non Finnish (NFE)

AF:

0.405

AC:

449706

AN:

1110000

Other (OTH)

AF:

0.405

AC:

24391

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

16101

32202

48303

64404

80505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.378

AC:

57355

AN:

151890

Hom.:

11078

Cov.:

AF XY:

0.373

AC XY:

27662

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.343

AC:

14201

AN:

41404

American (AMR)

AF:

0.323

AC:

4933

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.424

AC:

1473

AN:

3472

East Asian (EAS)

AF:

0.440

AC:

2258

AN:

5136

South Asian (SAS)

AF:

0.371

AC:

1783

AN:

4806

European-Finnish (FIN)

AF:

0.327

AC:

3458

AN:

10564

Middle Eastern (MID)

AF:

0.449

AC:

131

AN:

292

European-Non Finnish (NFE)

AF:

0.411

AC:

27908

AN:

67934

Other (OTH)

AF:

0.385

AC:

810

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1815

3630

5444

7259

9074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.407

Hom.:

9870

Bravo

AF:

0.373

TwinsUK

AF:

0.410

AC:

1521

ALSPAC

AF:

0.390

AC:

1504

ESP6500AA

AF:

0.333

AC:

1321

ESP6500EA

AF:

0.399

AC:

3335

ExAC

AF:

0.386

AC:

46651

Asia WGS

AF:

0.369

AC:

1283

AN:

3478

EpiCase

AF:

0.409

EpiControl

AF:

0.405

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T;.;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.81

.;T;T;T

MetaRNN

Benign

0.0032

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

2.0

M;M;.;.

PhyloP100

2.3

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Benign

0.067

Sift

Uncertain

0.029

D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.31

MPC

0.17

ClinPred

0.021

GERP RS

2.9

Varity_R

0.23

gMVP

0.79

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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NM_001495.5:c.1385T>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over