dbSNP rs2245020: GFRA1:p.Asn184Asn (chr10-116125439-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_005264.8(GFRA1):c.552C>T(p.Asn184Asn) 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 (no stars).

Frequency

Genomes: 𝑓 0.50 ( 20162 hom., cov: 34)

Exomes 𝑓: 0.56 ( 232100 hom. )

Consequence

GFRA1
NM_005264.8 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.282

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 (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 no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
GFRA1	NM_005264.8 link	c.552C>T	p.Asn184Asn	synonymous_variant	Exon 6 of 11	ENST00000355422.11	NP_005255.1	P56159-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422.11 link	c.552C>T	p.Asn184Asn	synonymous_variant	Exon 6 of 11	5	NM_005264.8	ENSP00000347591.6		P56159-1

Frequencies

GnomAD3 genomes

AF:

0.498

AC:

75653

AN:

151998

Hom.:

20153

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.561

AC XY:

407684

AN XY:

727026

show subpopulations

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.:

AF XY:

0.502

AC XY:

37299

AN XY:

74350

show subpopulations

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: no assertion criteria provided

LINK: link

Submissions by phenotype

GFRA1-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

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