rs8192662

Positions:

chr10-116270903-A-T

Variant summary

Our verdict is Benign. Variant got -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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 -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 id is 1328035.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-116270903-A-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422.11 link	c.253T>A	p.Tyr85Asn	missense_variant	3/11	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

GnomAD3 exomes

AF:

0.0274

AC:

6889

AN:

251248

Hom.:

177

AF XY:

0.0292

AC XY:

3970

AN XY:

135832

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 SAS exome

AF:

0.0413

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

Gnomad4 AFR exome

AF:

0.00526

Gnomad4 AMR exome

AF:

0.0187

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0414

Gnomad4 FIN exome

AF:

0.0458

Gnomad4 NFE exome

AF:

0.0322

Gnomad4 OTH exome

AF:

0.0301

GnomAD4 genome

AF:

0.0239

AC:

3647

AN:

152336

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1886

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00618

Gnomad4 AMR

AF:

0.0286

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0366

Gnomad4 FIN

AF:

0.0493

Gnomad4 NFE

AF:

0.0311

Gnomad4 OTH

AF:

0.0198

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

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

GFRA1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2024

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

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

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