Genetic Variant GFRA1:p.Asn184Lys (chr10-116125439-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005264.8(GFRA1):c.552C>A(p.Asn184Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N184S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GFRA1
NM_005264.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.282

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

renal hypodysplasia/aplasia 4
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

GFRA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40947983).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005264.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GFRA1	NM_005264.8	MANE Select	c.552C>A	p.Asn184Lys	missense	Exon 6 of 11	NP_005255.1
GFRA1	NM_001348098.4		c.552C>A	p.Asn184Lys	missense	Exon 6 of 11	NP_001335027.1
GFRA1	NM_001145453.4		c.537C>A	p.Asn179Lys	missense	Exon 5 of 10	NP_001138925.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.552C>A	p.Asn184Lys	missense	Exon 6 of 11	ENSP00000347591.6
GFRA1	ENST00000369236.5	TSL:1	c.537C>A	p.Asn179Lys	missense	Exon 4 of 9	ENSP00000358239.1
GFRA1	ENST00000369234.5	TSL:5	c.552C>A	p.Asn184Lys	missense	Exon 6 of 11	ENSP00000358237.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727106

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111844

Other (OTH)

AF:

0.00

AC:

AN:

60386

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

34913

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.74

M_CAP

Benign

0.045

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.1

PhyloP100

-0.28

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.72

REVEL

Benign

0.15

Sift

Benign

0.31

Sift4G

Benign

0.71

Polyphen

0.76

Vest4

0.47

MutPred

0.44

Gain of methylation at N184 (P = 0.0244)

MVP

0.47

MPC

0.48

ClinPred

0.39

GERP RS

-2.0

Varity_R

0.23

gMVP

0.50

Mutation Taster

=58/42

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over