10-116089842-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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 (★). 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.73

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=0.0017496347).
• 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 criteria_provided_single_submitter, 1 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	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	c.1096A>G	p.Thr366Ala	missense_variant	9/11	5	NM_005264.8	A2

Frequencies

GnomAD3 genomes AF: 0.0941 AC: 14309 AN: 152040 Hom.: 703 Cov.: 32

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

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.: 33 AF XY: 0.0950 AC XY: 69038 AN XY: 726944

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.: 32 AF XY: 0.0956 AC XY: 7112 AN XY: 74388

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: criteria provided, single submitter

Submissions by phenotype

GFRA1-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	18
Dann	Benign	0.75
Eigen	Benign	-0.082
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.026	P;P;P;P
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs2072276; hg19: chr10-117849353; COSMIC: COSV62602392;