Variant 10-116089842-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA1	NM_005264.8 linkuse as main transcript	c.1096A>G	p.Thr366Ala	missense_variant	9/11	ENST00000355422.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA1	ENST00000355422.11 linkuse as main transcript	c.1096A>G	p.Thr366Ala	missense_variant	9/11	5	NM_005264.8	A2	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

GnomAD3 exomes

AF:

0.104

AC:

26244

AN:

251218

Hom.:

1516

AF XY:

0.104

AC XY:

14157

AN XY:

135784

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 SAS exome

AF:

0.135

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

Gnomad4 AFR exome

AF:

0.0872

Gnomad4 AMR exome

AF:

0.135

Gnomad4 ASJ exome

AF:

0.0829

Gnomad4 EAS exome

AF:

0.157

Gnomad4 SAS exome

AF:

0.137

Gnomad4 FIN exome

AF:

0.0881

Gnomad4 NFE exome

AF:

0.0865

Gnomad4 OTH exome

AF:

0.0970

GnomAD4 genome

AF:

0.0941

AC:

14318

AN:

152160

Hom.:

704

Cov.:

AF XY:

0.0956

AC XY:

7112

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0876

Gnomad4 AMR

AF:

0.106

Gnomad4 ASJ

AF:

0.0985

Gnomad4 EAS

AF:

0.150

Gnomad4 SAS

AF:

0.136

Gnomad4 FIN

AF:

0.0901

Gnomad4 NFE

AF:

0.0881

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.0895

Hom.:

950

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

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

GFRA1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.14

.;.;T;T

Eigen

Benign

-0.082

Eigen_PC

Benign

0.072

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.61

.;T;.;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;.;L;L

MutationTaster

Benign

0.026

P;P;P;P

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.2

N;.;.;.

REVEL

Benign

0.060

Sift

Benign

0.92

T;.;.;.

Sift4G

Benign

0.86

T;T;T;T

Polyphen

0.37

B;B;B;B

Vest4

0.083

MPC

0.39

ClinPred

0.018

GERP RS

5.0

Varity_R

0.087

gMVP

0.50

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

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