rs8192662

chr10-116270903-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Benign criteria provided, single submitter B:3
• 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]

ACMG classification

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 GnomAd 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: 3649 AN: 152218 Hom.: 56 Cov.: 33

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

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.: 33 AF XY: 0.0314 AC XY: 22805 AN XY: 727156

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.: 56 Cov.: 33 AF XY: 0.0253 AC XY: 1886 AN XY: 74492

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.: 30

Bravo AF: 0.0205

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.0324 AC: 279

ExAC AF: 0.0273 AC: 3316

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0319

EpiControl AF: 0.0327

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

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, 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.0087	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
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	T
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

Other links and lift over

dbSNP: rs8192662; hg19: chr10-118030415;