rs2072276

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_005264.8(GFRA1):c.1096A>G(p.Thr366Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0936 in 1,613,376 control chromosomes in the GnomAD database, including 7,578 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.094 ( 704 hom., cov: 32)

Exomes 𝑓: 0.094 ( 6874 hom. )

Consequence

GFRA1
NM_005264.8 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.73

Publications

19 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

GFRA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017496347).

BP6

Variant 10-116089842-T-C is Benign according to our data. Variant chr10-116089842-T-C is described in ClinVar as Benign. ClinVar VariationId is 3060080.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005264.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFRA1	NM_005264.8	MANE Select	c.1096A>G	p.Thr366Ala	missense	Exon 9 of 11	NP_005255.1	P56159-1
GFRA1	NM_001348098.4		c.1096A>G	p.Thr366Ala	missense	Exon 9 of 11	NP_001335027.1	P56159-1
GFRA1	NM_001145453.4		c.1081A>G	p.Thr361Ala	missense	Exon 8 of 10	NP_001138925.1	P56159-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.1096A>G	p.Thr366Ala	missense	Exon 9 of 11	ENSP00000347591.6	P56159-1
GFRA1	ENST00000369236.5	TSL:1	c.1081A>G	p.Thr361Ala	missense	Exon 7 of 9	ENSP00000358239.1	P56159-2
GFRA1	ENST00000369234.5	TSL:5	c.1096A>G	p.Thr366Ala	missense	Exon 9 of 11	ENSP00000358237.4	P56159-1

Frequencies

GnomAD3 genomes

AF:

0.0941

AC:

14309

AN:

152040

Hom.:

703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0876

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.0985

Gnomad EAS

AF:

0.150

Gnomad SAS

AF:

0.137

Gnomad FIN

AF:

0.0901

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.0881

Gnomad OTH

AF:

0.109

GnomAD2 exomes

AF:

0.104

AC:

26244

AN:

251218

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.0891

Gnomad AMR exome

AF:

0.137

Gnomad ASJ exome

AF:

0.0810

Gnomad EAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.0850

Gnomad NFE exome

AF:

0.0870

Gnomad OTH exome

AF:

0.104

GnomAD4 exome

AF:

0.0935

AC:

136671

AN:

1461216

Hom.:

6874

Cov.:

AF XY:

0.0950

AC XY:

69038

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.0872

AC:

2919

AN:

33466

American (AMR)

AF:

0.135

AC:

6056

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0829

AC:

2167

AN:

26132

East Asian (EAS)

AF:

0.157

AC:

6237

AN:

39698

South Asian (SAS)

AF:

0.137

AC:

11824

AN:

86246

European-Finnish (FIN)

AF:

0.0881

AC:

4706

AN:

53400

Middle Eastern (MID)

AF:

0.128

AC:

739

AN:

5768

European-Non Finnish (NFE)

AF:

0.0865

AC:

96169

AN:

1111412

Other (OTH)

AF:

0.0970

AC:

5854

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

6823

13646

20468

27291

34114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3672

7344

11016

14688

18360

<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:

0.0941

AC:

14318

AN:

152160

Hom.:

704

Cov.:

AF XY:

0.0956

AC XY:

7112

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0876

AC:

3636

AN:

41520

American (AMR)

AF:

0.106

AC:

1626

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0985

AC:

342

AN:

3472

East Asian (EAS)

AF:

0.150

AC:

775

AN:

5156

South Asian (SAS)

AF:

0.136

AC:

656

AN:

4818

European-Finnish (FIN)

AF:

0.0901

AC:

954

AN:

10592

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0881

AC:

5993

AN:

68006

Other (OTH)

AF:

0.111

AC:

233

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

667

1334

2001

2668

3335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<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:

0.0906

Hom.:

2115

Bravo

AF:

0.0958

TwinsUK

AF:

0.0906

AC:

336

ALSPAC

AF:

0.0820

AC:

316

ExAC

AF:

0.103

AC:

12514

Asia WGS

AF:

0.149

AC:

518

AN:

3478

EpiCase

AF:

0.0929

EpiControl

AF:

0.0907

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

GFRA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.14

Eigen

Benign

-0.082

Eigen_PC

Benign

0.072

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

3.7

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.2

REVEL

Benign

0.060

Sift

Benign

0.92

Sift4G

Benign

0.86

Polyphen

0.37

Vest4

0.083

MPC

0.39

ClinPred

0.018

GERP RS

5.0

Varity_R

0.087

gMVP

0.50

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over