rs2245020

chr10-116125439-G-Achr10-116125439-G-Cchr10-116125439-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_005264.8(GFRA1):c.552C>T(p.Asn184=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 1,613,566 control chromosomes in the GnomAD database, including 252,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.50 (20162 hom., cov: 34)
  • Exomes 𝑓: 0.56 (232100 hom.)
• Consequence: GFRA1 NM_005264.8 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.282

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-116125439-G-A is Benign according to our data. Variant chr10-116125439-G-A is described in ClinVar as [Benign]. Clinvar id is 3060424.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.282 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA1	NM_005264.8	c.552C>T	p.Asn184=	synonymous_variant	6/11	ENST00000355422.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA1	ENST00000355422.11	c.552C>T	p.Asn184=	synonymous_variant	6/11	5	NM_005264.8	A2

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75653 AN: 151998 Hom.: 20153 Cov.: 34

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.525

GnomAD3 exomes AF: 0.568 AC: 142471 AN: 250954 Hom.: 41380 AF XY: 0.568 AC XY: 77010 AN XY: 135646

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.701

Gnomad ASJ exome AF: 0.578

Gnomad EAS exome AF: 0.585

Gnomad SAS exome AF: 0.559

Gnomad FIN exome AF: 0.572

Gnomad NFE exome AF: 0.563

Gnomad OTH exome AF: 0.566

GnomAD4 exome AF: 0.561 AC: 819886 AN: 1461448 Hom.: 232100 Cov.: 55 AF XY: 0.561 AC XY: 407684 AN XY: 727026

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.693

Gnomad4 ASJ exome AF: 0.570

Gnomad4 EAS exome AF: 0.568

Gnomad4 SAS exome AF: 0.555

Gnomad4 FIN exome AF: 0.575

Gnomad4 NFE exome AF: 0.563

Gnomad4 OTH exome AF: 0.551

GnomAD4 genome AF: 0.498 AC: 75682 AN: 152118 Hom.: 20162 Cov.: 34 AF XY: 0.502 AC XY: 37299 AN XY: 74350

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.626

Gnomad4 ASJ AF: 0.562

Gnomad4 EAS AF: 0.573

Gnomad4 SAS AF: 0.559

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.561

Gnomad4 OTH AF: 0.527

Alfa AF: 0.540 Hom.: 28347

Bravo AF: 0.494

Asia WGS AF: 0.564 AC: 1960 AN: 3478

EpiCase AF: 0.565

EpiControl AF: 0.557

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 17, 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
BayesDel_noAF	Benign	-0.54
Cadd	Benign	1.1
Dann	Benign	0.91

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: rs2245020; hg19: chr10-117884950; COSMIC: COSV62603718;