chr10-116270903-A-T
Position:
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 same amino acid change has been previously reported as Likely benignin UniProt.
Frequency
Genomes: 𝑓 0.024 ( 56 hom., cov: 33)
Exomes 𝑓: 0.031 ( 819 hom. )
Consequence
GFRA1
NM_005264.8 missense
NM_005264.8 missense
Scores
2
8
6
Clinical Significance
Conservation
PhyloP100: 7.19
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]
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 | UniProt |
---|---|---|---|---|---|---|---|
GFRA1 | NM_005264.8 | c.253T>A | p.Tyr85Asn | missense_variant | 3/11 | ENST00000355422.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GFRA1 | ENST00000355422.11 | c.253T>A | p.Tyr85Asn | missense_variant | 3/11 | 5 | NM_005264.8 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0240 AC: 3649AN: 152218Hom.: 56 Cov.: 33
GnomAD3 genomes
AF:
AC:
3649
AN:
152218
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0274 AC: 6889AN: 251248Hom.: 177 AF XY: 0.0292 AC XY: 3970AN XY: 135832
GnomAD3 exomes
AF:
AC:
6889
AN:
251248
Hom.:
AF XY:
AC XY:
3970
AN XY:
135832
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0310 AC: 45270AN: 1461694Hom.: 819 Cov.: 33 AF XY: 0.0314 AC XY: 22805AN XY: 727156
GnomAD4 exome
AF:
AC:
45270
AN:
1461694
Hom.:
Cov.:
33
AF XY:
AC XY:
22805
AN XY:
727156
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0239 AC: 3647AN: 152336Hom.: 56 Cov.: 33 AF XY: 0.0253 AC XY: 1886AN XY: 74492
GnomAD4 genome
AF:
AC:
3647
AN:
152336
Hom.:
Cov.:
33
AF XY:
AC XY:
1886
AN XY:
74492
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
128
ALSPAC
AF:
AC:
139
ESP6500AA
AF:
AC:
35
ESP6500EA
AF:
AC:
279
ExAC
AF:
AC:
3316
Asia WGS
AF:
AC:
32
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
GFRA1-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 20, 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
M;M;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
P;P;P;P
Vest4
MPC
1.3
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at