Variant 20-3661136-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022139.4(GFRA4):c.200C>G(p.Ala67Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000677 in 1,330,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Consequence

GFRA4
NM_022139.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.53

Variant links:

Genes affected

GFRA4 (HGNC:13821): (GDNF family receptor alpha 4) The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for persephin, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for RET-associated diseases. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

GFRA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GFRA4	NM_022139.4 linkuse as main transcript	c.200C>G	p.Ala67Gly	missense_variant	2/6	ENST00000290417.7
GFRA4	NM_145762.3 linkuse as main transcript	c.200C>G	p.Ala67Gly	missense_variant	2/5
GFRA4	XM_005260793.2 linkuse as main transcript	c.200C>G	p.Ala67Gly	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA4	ENST00000290417.7 linkuse as main transcript	c.200C>G	p.Ala67Gly	missense_variant	2/6	1	NM_022139.4	P1	Q9GZZ7-2
GFRA4	ENST00000319242.8 linkuse as main transcript	c.200C>G	p.Ala67Gly	missense_variant	2/5	1			Q9GZZ7-1
GFRA4	ENST00000477160.1 linkuse as main transcript	c.200C>G	p.Ala67Gly	missense_variant, NMD_transcript_variant	2/4	1			Q9GZZ7-3

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151750

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.49e-7

AC:

AN:

1178376

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

570830

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000208

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151750

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74128

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.200C>G (p.A67G) alteration is located in exon 2 (coding exon 2) of the GFRA4 gene. This alteration results from a C to G substitution at nucleotide position 200, causing the alanine (A) at amino acid position 67 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.89

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.58

Sift

Benign

0.064

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.55

MutPred

0.63

Loss of stability (P = 0.044);Loss of stability (P = 0.044);

MVP

0.74

MPC

1.0

ClinPred

0.98

GERP RS

4.1

Varity_R

0.46

gMVP

0.73

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