rs8192662

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_005264.8(GFRA1):c.253T>A(p.Tyr85Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0303 in 1,614,030 control chromosomes in the GnomAD database, including 875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.024 ( 56 hom., cov: 33)

Exomes 𝑓: 0.031 ( 819 hom. )

Consequence

GFRA1
NM_005264.8 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:4

Conservation

PhyloP100: 7.19

Publications

12 publications found

Variant links:

Genes affected

GFRA1 (HGNC:4243): (GDNF family receptor alpha 1) This gene encodes a member of the glial cell line-derived neurotrophic factor receptor (GDNFR) family of proteins. The encoded preproprotein is proteolytically processed to generate the mature receptor. 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. This receptor is a glycosylphosphatidylinositol (GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for Hirschsprung disease. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

GFRA1 Gene-Disease associations (from GenCC):

renal hypodysplasia/aplasia 4
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

GFRA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008683264).

BP6

Variant 10-116270903-A-T is Benign according to our data. Variant chr10-116270903-A-T is described in ClinVar as Benign. ClinVar VariationId is 1328035.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0239 (3647/152336) while in subpopulation SAS AF = 0.0366 (177/4832). AF 95% confidence interval is 0.0322. There are 56 homozygotes in GnomAd4. There are 1886 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFRA1	NM_005264.8 link	c.253T>A	p.Tyr85Asn	missense_variant	Exon 3 of 11	ENST00000355422.11	NP_005255.1	P56159-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422.11 link	c.253T>A	p.Tyr85Asn	missense_variant	Exon 3 of 11	5	NM_005264.8	ENSP00000347591.6		P56159-1

Frequencies

GnomAD3 genomes

AF:

0.0240

AC:

3649

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00620

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0286

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0364

Gnomad FIN

AF:

0.0493

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0311

Gnomad OTH

AF:

0.0205

GnomAD2 exomes

AF:

0.0274

AC:

6889

AN:

251248

AF XY:

0.0292

show subpopulations

Gnomad AFR exome

AF:

0.00560

Gnomad AMR exome

AF:

0.0175

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0514

Gnomad NFE exome

AF:

0.0303

Gnomad OTH exome

AF:

0.0280

GnomAD4 exome

AF:

0.0310

AC:

45270

AN:

1461694

Hom.:

819

Cov.:

AF XY:

0.0314

AC XY:

22805

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00526

AC:

176

AN:

33476

American (AMR)

AF:

0.0187

AC:

836

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

504

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0414

AC:

3568

AN:

86256

European-Finnish (FIN)

AF:

0.0458

AC:

2443

AN:

53284

Middle Eastern (MID)

AF:

0.0284

AC:

164

AN:

5768

European-Non Finnish (NFE)

AF:

0.0322

AC:

35754

AN:

1111956

Other (OTH)

AF:

0.0301

AC:

1820

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

2822

5643

8465

11286

14108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1368

2736

4104

5472

6840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0239

AC:

3647

AN:

152336

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1886

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00618

AC:

257

AN:

41596

American (AMR)

AF:

0.0286

AC:

438

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.0366

AC:

177

AN:

4832

European-Finnish (FIN)

AF:

0.0493

AC:

524

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0311

AC:

2118

AN:

68022

Other (OTH)

AF:

0.0198

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

190

380

570

760

950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0280

Hom.:

Bravo

AF:

0.0205

TwinsUK

AF:

0.0345

AC:

128

ALSPAC

AF:

0.0361

AC:

139

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.0324

AC:

279

ExAC

AF:

0.0273

AC:

3316

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0319

EpiControl

AF:

0.0327

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GFRA1-related disorder

Benign:1

May 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

.;.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

.;D;.;D

MetaRNN

Benign

0.0087

T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.9

M;M;M;M

PhyloP100

7.2

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.8

D;D;D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D

Polyphen

0.55

P;P;P;P

Vest4

0.27

MPC

1.3

ClinPred

0.044

GERP RS

4.0

Varity_R

0.78

gMVP

0.77

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over